Methods of treatment with lxr modulators

ABSTRACT

Disclosed are methods of using compounds that modulate LXR.

FIELD OF THE INVENTION

This invention relates to novel treatments and, in particular, tomethods for the promotion of growth and/or repair of neurons in diseasesor conditions characterised by neuron degeneration, injury or impairedplasticity.

BACKGROUND OF THE INVENTION

The process of neurodegeneration is an important factor in manyneurological diseases including acute disease such as stroke, traumaticbrain injury and spinal cord injury as well as chronic disease includingAlzheimer's disease, fronto-temporal dementias (tauopathies), peripheralneuropathy, Parkinson's disease, dementia with Lewy bodies, Huntington'sdisease, amyotrophic lateral sclerosis and multiple sclerosis. Agentsoffering neuroprotection, reduction of inflammatory response orenhancement of functional recovery may be useful in the treatment ofthese diseases. At present there are no treatments available whichpromote regeneration following neuronal damage due to such CNS diseases.

The mechanisms underlying functional recovery are currently unknown.Mechanisms thought to promote functional recovery include the sproutingof injured or non-injured axons, enhanced synaptic plasticity,differentiation of endogenous stem cells, activation of redundantpathways, changes in receptor distribution or excitability of neurons orglia (1,2).

Additionally, inflammation in the brain is increasingly seen as animportant contributor to neurodegenerative disease mechanisms.Experimental and clinical damage to the brain leads to rapidupregulation of an array of pro-inflammatory mediators such asprostaglandin E2 (PGE2), tumour necrosis factor alpha (TNFα), nitricoxide (NO) and interleukin 6 (IL6). These factors are predominantlysecreted by activated glia and exert many neurotoxic actions. Thuspreventing or reducing inflammatory processes may also promotefunctional recovery (3).

Following the onset of stroke, some degree of spontaneous functionalrecovery is observed in many patients, suggesting that the brain has theability to repair and/or remodel following injury. Agents that have thepotential to enhance this recovery may therefore allow intervention tobe made much later (potentially days) following the onset of cerebralischaemia. Therapies that elicit axon sprouting following injury maytherefore be valuable in restoring functional synaptic connections lostby the degenerating CNS in chronic and acute neurodegenerative diseases.

Finally, diseases where increased synaptic plasticity may also bebeneficial are the psychiatric disorders including schizophrenia anddepression. It has been reported that patients undergoing chronictreatment with effective anti-depressants display increased markers ofsynaptic plasticity. Compounds which enhance the ability of neurons toextend neurites and potentially increase neuroplasticity may thereforebe effective in the prophylaxis and treatment of these disorders.

LXRα and LXRβ (collectively LXR) are nuclear hormone receptors thatregulate the metabolism of several important lipids, includingcholesterol (4). The nucleotide and amino acid sequences of LXRα areshown in FIGS. 3 and 4 (SEQ ID NOs:1 and 2), respectively. Thenucleotide and amino acid sequences of LXRβ are shown in FIGS. 5 and 6(SEQ ID NOs:3 and 4), respectively. The LXRs regulate the expression oftarget genes by binding to short stretches of DNA, termed LXRβ responseelements (LXREs), as heterodimers with the retinoid X receptors(RXR)(5-8). LXREs have been identified in the regulatory regions of anumber of genes involved in cholesterol homeostasis including CYP7A1(9), which catalyses the first and rate-limiting step in bile acidbiosynthesis, the cholesterol ester transport protein (10), thetranscription factor SREBP-1C (11,12), apolipoprotein E (apoE)(13).LXREs have also been identified in the genes encoding the ATP bindingcassette transporters (ABC) A1 and G1(14-18), which mediate the effluxof phospholipids and cholesterol from macrophages, intestinalenterocytes and other cell types.

Currently, patients with elevated levels of cholesterol are treatedusing the compounds that inhibit the body's endogenous cholesterolsynthesis. As important components of the complex system that regulatescholesterol levels in the body the LXRs have also been proposed astargets for the prophylaxis and treatment of hypercholesteraemia (raisedlevels of plasma cholesterol) and its associated atheroscleroticdiseases.

Schmidt, et al. (19) found that LXRβ activators5-tetradecyloxy-2-furancarboxylic acid (TOFA) and22(R)-hydroxycholesterol stimulated transcription from promoters underthe control of AP-1 or NF-KB transcription factor binding sites andinduced neuronal differentiation in rat pheochromocytoma cells.

It has now been found that LXR mRNA levels are elevated followingtransient middle cerebral artery occlusion (tMCAO) in the rat.

Administration of LXR agonists enhances neurite outgrowth in primarycultures of hippocampal and cortical neurons; limits the inflammatoryresponse in microglial cells and upregulates the expression of LXRtarget genes in glial cells. LXR agonist administration also leads toincreased cholesterol efflux from primary cell cultures of astrocytesand thus may promote synaptic plasticity.

The LXR target genes ABCA1, ApoE, ABCG1 and SREBP1c are known to beexpressed in the CNS. In vivo the central administration of LXR agonistshas been found to increase gene expression of some LXR target genes inthe CNS.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides the use of an LXR agonistin the manufacture of medicaments for the treatment and/or prevention ofdiseases or conditions characterised by neuron degeneration;inflammation in the CNS, injury or impaired plasticity.

In another aspect, the present invention provides a method for treatinga patient suffering from a disease selected from the group consistingof: stroke, Alzheimer's disease, fronto-temporal dementias, peripheralneuropathy, Parkinson's disease, dementia with Lewy bodies, Huntington'sdisease, amyotrophic lateral sclerosis, and multiple sclerosis, saidmethod comprising the step of administering to said patient an effectiveamount of an LXR modulator in combination with a carrier.

In yet another aspect, the present invention provides a method forpromoting cholesterol efflux in at least one astroglial cell, saidmethod comprising the step of: contacting said at least one astroglialcell with a cholesterol-efflux-promoting effective amount of an LXRmodulator in combination with a carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that LXR alpha mRNA levels were elevated in brains fromtMCAO animals compared to sham-operated controls at 1 and 2 weekspost-surgery. The timepoints at which this elevation in mRNA levels isseen corresponds to the recovery period following MCAO in the rat inwhich a degree of spontaneous recovery is observed (20).

FIG. 2 shows that an LXR agonist (Example 1) can inhibit the secretionof pro-inflammatory mediators (IL-6, PGE2, TNF-α and NO) from LPS\INF-γstimulated microglia cells.

FIG. 3 shows the nucleotide sequence of human LXRα (SEQ ID NO:1) fromGenebank, accession NM_(—)005693.

FIG. 4 shows the deduced amino acid sequence of human LXRα (SEQ ID NO:2)from Genebank accession NP_(—)005684.

FIG. 5 shows the nucleotide sequence of human LXRβ (SEQ ID NO:3) fromGenbank accession XM_(—)046419.

FIG. 6 shows the deduced amino acid sequence of human LXRβ (SEQ D NO:4)from Genebank accession XP_(—)046419.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred aspect of the invention, the LXR agonists are selectedfrom those disclosed in International Patent Applications WO 01/54759(Tularik Inc. US), PCT/US01/27622 (SmithKline Beecham plc UK), WO01/41704 (Merck & CO., INC) and WO97/28137 (Merck & CO., INC).

International Patent Application WO 00/54759 (Tularik Inc. US) disclosescompounds of formula (1):

wherein:

-   Ar represents an aryl group; R¹ is —OH, —O—(C₁-C₇)alkyl,    —OC(O)—(C₁-C₇)alkyl, —O—(C₁-C₇)heteroalkyl, —OC(O)—    (C₁-C₇)heteroalkyl, —CO₂H, —NH₂, —NH(C₁-C₇)alkyl, —N((C₁-C₇)alkyl)₂    or —NH—S(O)₂—(C₁-C₅)alkyl;-   R² is (C₁-C₇)alkyl, (C₁-C₇)heteroalkyl, aryl and aryl(C₁-C₇)alkyl;-   X¹, X², X³, X⁴, X⁵ and X⁶ are each independently H, (C₁-C₅)alkyl,    (C₁-C₅)hetroalkyl, F or Cl, with the proviso that no more than three    of X¹ through X⁶ are H, (C₁-C₅)alkyl or (C₁-C₅)heteroalkyl; and-   Y is —N(R¹²)S(O)_(m)—, —N(R¹²)S(O)_(m)N(R¹³)—, —N(R¹²)C(O)—,    —N(R¹²)C(O)N(R¹³)—, —N(R¹²)C(S)— or —N(R¹²)C(O)O—, wherein R12 and    R13 are each independently hydrogen, (C₁-C₇)aryl,    (C₁-C₇)heteroalkyl, aryl and aryl(C₁-C₇)alkyl, and optionally when Y    is —N(R¹²)S(O)_(m), or —N(R¹²)S(O)_(m)N(R¹³)—, R¹² forms a five, six    or seven-membered ring fused to Ar or to R² through covalent    attachment to Ar or R², respectively. In the above Y groups, the    subscript m is an integer of from 1 to 2,    as being useful as agonists of LXR and their use in pharmaceutical    formulations to reverse cholesterol transport and treat    atherosclerotic cardiovascular diseases and related diseases.

With respect to the compounds of formula (I) the term “alkyl”, by itselfor as part of another substituent, means, unless otherwise stated, astraight or branched chain, or cyclic hydrocarbon radical, orcombination thereof, which may be fully saturated, mono- orpolyunsaturated and can include di- and multi-radicals, having thenumber of carbons designated (i.e., C₁₋₁₀ means one to ten carbons).Examples of saturated hydrocarbon radicals include groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl,cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomersof, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. The term “alkyl”, unless otherwise noted,is also meant to include those derivatives of alkyl defined in moredetail below as “cycloalkyl” and “alkylene”. The term “alkylene” byitself or as part of another substituent means a divalent radicalderived from alkane, as exemplified by —CH₂CH₂CH₂CH₂—. Typically, analkyl group will have from 1 to 24 carbon atoms, with those having 10 orfewer carbon atoms being preferred. A “lower alkyl” or “lower alkylene”is a shorter chain alkyl or alkylene group, generally having eight orfewer carbon atoms, preferably four or fewer carbon atoms.

The term “alkoxy”, employed alone or in combination with other termsmeans, unless otherwise stated, an alkyl group, as defined above,connected to the remainder of the molecule via an oxygen atom, such as,for example, methoxy, ethoxy, 1-propoxy, 2-propoxy, and the higherhomologs and isomers.

The term “heteroalkyl”, by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si, S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quarternized. The heteroatom(s) O, N and S may be placedat any position of the heteroalkyl group except for the position atwhich the alkyl group is attached to the remainder of the molecule.Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃),—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Also included in the term “heteroalkyl” are thoseradicals described in more detail below as “heteroalkylene” and“heterocycloalkyl.” The term “heteroalkylene by itself or as part ofanother substituent means a divalent radical derived from heteroalkyl,as exemplified by —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini. Still further, for alkylene and heteroalkylene linkinggroups, as well as all other linking groups described herein, nospecific orientation of the linking group is implied.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalky” respectively. The terms“cycloalkyl” and “heterocycloalkyl” are also meant to include bicyclic,tricyclic and polycyclic versions thereof. Additionally, forheterocycloalkyl, a heteroatom may occupy the position at which theheterocyclyl is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexyl, 3-cyclohexyl,cyclopentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, andthe like. Example of heterocycloalkyl include1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl,1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine or iodine atom. Additionally, terms such as “fluoroalkyl”, aremeant to include monofluoroalkyl and polyfluoroalkyl.

The term “aryl”, employed alone or in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated,an aromatic substituent which can be a single ring or multiple rings (upto three rings) which are fused together or linked covalently. The ringsmay each contain from zero to four heteroatoms selected from N, O and S,wherein the nitrogen and sulfur atoms are optionally oxidized, and thenitrogen atom(s) are optionally quaternized. The aryl groups thatcontain heteroatoms may be referred to as “heteroaryl” and can beattached to the remainder of the molecule through a carbon atom or aheteroatom. Non-limiting examples of aryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolinyl, and 6-quinolinyl. Substituents for each of the above notedaryl ring systems are selected form the group of acceptable substituentsdescribed below.

The terms “arylalkyl” and “arylheteroalkyl” are meant to include thoseradicals in which an aryl group is attached to an aryl group (e.g.,benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group(e.g. phenoxymethyl, 2-pyridyloxymethyl, 1-napthyloxy-3-propyl, and thelike). The arylaklyl and arylheteroalkyl groups will typically containfrom 1 to 3 aryl moieties attached to the alkyl or heteroalkyl portionby a covalent bond or by fusing the ring to, for example, a cycloalkylor heterocycloalkyl group. For arylheteroalkyl groups, a heteroatom canoccupy the position at which the group is attached to the remainder ofthe molecule. For example, the term “arylheteroalkyl” is meant toinclude benzyloxy, 2-phenylethoxy, phenethylamine, and the like.

Each of the above terms (e.g., “alkyl”, “heteroalkyl”, “aryl” etc) ismeant to include both substituted and unsubstituted forms of theindicated radical. Preferable substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andhetercycloalkenyl) can be a variety of groups selected from: —OR, ═O,═NR′, N—OR′, NR′R″, —SR′, -halogen, —SiR′RR′″, —OC(O)R′, —CO_(2R)′;—CONR′R″, OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)NR′R″, —NR″C(O)₂R′,NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NH—, C(NH₂)═NR′, S(O)R′, —S(O)₂R″,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such a radical. Preferably,substituted alkyl groups will have from one to six independentlyselected substituents, more preferably from one to four independentlyselected substituents, most preferably from one to three independentlyselected substituents. In the substituents listed above, R′, R″ and R′″each independently refer to hydrogen, unsubstituted (C₁₋₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups or aryl-(C₁₋₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl.

Similarly, substituents for the aryl groups are varied and selectedfrom: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR″C(O)NR′R′″,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SOR′, —S(O)₂R′,—S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluor(C₁₋₄)alkoxy, andperfluoro(C₁₋₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′ and R″ areindependently selected from hydrogen, (C₁₋₈)alkyl and heteroalkyl,unsubstituted aryl, (unsubstituted aryl)-(C₁₋₄)alkyl, and (unsubstitutedaryl)oxy-(C₁₋₄)alkyl. Preferably, substituted aryl groups will have fromone to four independently selected substituents, more preferably fromone to three independently selected substituents, most preferably fromone to two independently selected substituents.

Two of the substituents on adjacent atoms of the aryl ring mayoptionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)-U-, wherein T and U are independently —NH—, —O—, CH₂or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl ring may optionally bereplaced with a substituent of formula -A-(CH₂)r-B—, wherein A and B areindependently —CH₂—, —O—, —NH—, S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the arylring may optionally be replaced with a substituent of the formula—(CH₂)_(S)—X—(CH₂)_(t)—, where s and t are integers of from 0 to 3, andX is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituent R′in —NR′— and S(O)₂NR′— selected from hydrogen or unsubstituted(C₁₋₆)alkyl.

The term “heteroatom” is meant to include oxygen (O), nitrogen (N),sulfur (S) and silicon (Si).

The term, “LXR modulator,” as used herein, means a small molecule thatmodulates the biological activities of LXRα and/or LXRβ. Morespecifically, such an LXR modulator either enhances or inhibits thebiological activities of LXR. If such a modulator partially orcompletely enhances the biological activities of LXR, it is a partial orcomplete LXR agonist, respectively. Conversely, if such a modulatoreither partially or completely inhibits the biological activities ofLXR, it is a partial or complete LXR antagonist, respectively.

Example 1 of WO 00/54759 (Tularik Inc. US) has the following structure:

Compounds of formula (I) can be prepared using readily availablestarting materials or known intermediates. WO 00/54759 describes anumber of possible synthetic routes for the production of suchcompounds, such as those depicted in scheme 1.

As shown in Scheme 1, aniline (I) (as representative of substitutedanilines and other arylamines) can be alkylated, acylated or arylated(general addition of R group) to form (ii), or the aromatic ring can bederivatized with, for example, hexafluoroacetone to form (iii).Treatment of (iii) with an appropriate alkylating group, acylating groupor arylating group provides (iv), which can be sulfonylated with, forexample, an appropriate sulfonyl halide to form (vi). Alternatively, theaniline derivative can be sufonylated to form (v), which can then bealkylated or acylated to form compounds of formula (vi).

Other compounds of formula (I) can be formed by treating the substitutedaniline (iv) (or iii), with reagents suitable for the formation ofamides (vii), carbamates (viii) and ureas (ix). Various reagents areuseful in the above scheme and can be found in, for example March,Advanced Organic Chemistry 4th ed. John Wiley & Sons, New York N.Y.(1992).

International Patent Application PCT/US01/27622 (SmithKline Beecham plc)discloses compounds of formula (II):

wherein:

-   X is OH or NH₂;-   p is 0-6;-   each R¹ and R² are the same or different and are each independently    selected from the group consisting of H, C₁₋₈alkyl, C₁₋₈alkoxy and    C₁₋₈thioalkyl;-   Z is CH or N;-   when Z is CH, k is 0-4;-   when Z is N, k is 0-3;-   each R³ is the same or different and is independently selected from    the group consisting of halo, —OH, C₁₋₈alkyl, C₂₋₈alkenyl,    C₁₋₈alkoxy, C₂₋₈alkenyloxy, —S(O)_(a)R⁶, —NR⁷R⁸, —COR⁶, COOR⁶,    R¹⁰COOR⁶, OR¹⁰COOR⁶, CONR⁷R⁸, —OC(O)R⁹, —R¹⁰NR⁷R⁸, —OR¹⁰NR⁷R⁸, 5-6    membered heterocycle, nitro, and cyano;    -   a is 0, 1 or 2;    -   R⁶ is selected from the group consisting of H, C₁₋₈alkyl,        C₁₋₈alkoxy and C₂₋₈alkenyl;    -   each R⁷ and R⁸ are the same or different and are each        independently selected from the group consisting of H,        C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₈alkynyl;    -   R⁹ is selected from the group consisting of H, C₁₋₈alkyl and        —NR⁷R⁸;    -   R¹⁰ is C₁₋₈alkyl;-   n is 2-8;-   q is 0 or 1;-   R⁴ is selected from the group consisting of H, C₁₋₈alkyl,    C₁₋₈alkenyl, and alkenyloxy;-   Ring A is selected from the group consisting of C₈cycloalkyl, aryl,    4-8 membered heterocycle, and 5-6 membered heteroaryl;-   each ring B is the same or different and is independently selected    from the group consisting of C₃₋₈cycloalkyl and aryl,-   as being useful as agonists of LXR and their use in pharmaceutical    formulations to reverse cholesterol transport and treat    atherosclerotic cardiovascular diseases and related diseases.

With respect to compounds of formula (II) the term “alkyl” refers toaliphatic straight or branched saturated hydrocarbon chains containingthe specified number of carbon atoms. Examples of “alkyl” groups as usedherein include but are not limited to methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and thelike. The term “alkyl” also refers to substituted alkyl wherein thesubstituents are selected from the group consisting of halo, —OR⁷ and—SR⁷, where R⁷ is H or C₁₋₈alkyl. This definition of “alkyl” is alsoapplicable to terms such as “thioalkyl” which incorporate the “alkyl”term. Thus, a “thioalkyl” as used herein refers to the group S—Ra whereRa is “alkyl” as defined.

The term “halo” refers to any halogen atom ie., fluorine, chlorine,bromine or iodine.

The term “alkenyl” refers to an aliphatic straight or branchedunsaturated hydrocarbon chain containing at least one and up to threecarbon-carbon double bonds. Examples of “alkenyl” groups as used hereininclude, but are not limited to, ethenyl and propenyl. The term“alkenyl” also refers to substituted alkenyl wherein the substituentsare selected from the group consisting of halo, —OR⁷ and —SR⁷, where R⁷is H or C₁₋₈alkyl.

The term “alkoxy” refers to a group O—Ra where Ra is “alkyl” as definedabove.

The term “alkenyloxy” refers to a group O—Rb where Rb is “alkenyl” asdefined above.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring havingthe specified number of carbon atoms and up to three carbon-carbondouble bonds. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclobutenyl, cyclopentenyl, cyclohexenyl and bicyclic cycloalkyl groupssuch as bicycloheptane and bicyclo(2.2.1)heptene. The term “cycloalkyl”also refers to substituted cycloalkyl wherein the ring bears one or moresubstituents selected from the group consisting of halo, —OH, C₁₋₈alkyl,C₂₋₈alkenyl, C₁₋₈alkoxy, C₂₋₈alkenyloxy, S(O)_(a)R⁶, —NR⁷R⁸, —COR⁶,—COOR⁶, —R¹⁰COOR⁶, —OR¹⁰COOR⁶, —CONR⁷R⁸, —OC(O)R⁹, —R¹⁰NR⁷R⁸,—OR¹⁰NR⁷R⁸, nitro, and cyano, wherein a is 0, 1 or 2; R⁶ is selectedfrom the group consisting of H, C₁₋₈alkyl, C₁₋₈alkoxy and C₂₋₈alkenyl;each R⁷ and R⁸ is the same or different and is independently selectedfrom the group consisting of H, C₁₋₈alkyl, C₂₋₈alkenyl and C₃₋₈alkynyl;R⁹ is selected from the group consisting of H, C₁₋₈alkyl and —NR⁷R⁸; andR¹⁰ is C₁₋₈alkyl. As will be appreciated by those skilled in the art,the number of possible substituents on the cycloalkyl ring will dependupon the size of ring. In one preferred embodiment, the cycloalkyl is acyclohexyl which may be substituted as described above.

The term “aryl” refers to aromatic groups selected from the groupconsisting of phenyl, 1-naphthyl and 2-naphthyl. The term “aryl” alsorefers to substituted aryl wherein the phenyl or naphthyl ring bears oneor more substituents selected from the group consisting of halo, —OH,C₁₋₈alkyl, C₂₋₈alkenyl, C₁₋₈alkoxy, C₂₋₈alkenyloxy, S(O)_(a)R⁶, —NR⁷R⁸,—COR⁶, —COOR⁶, —R¹⁰COOR⁶, —OR¹⁰COOR⁶, —CONR⁷R⁸, —OC(O)R⁹, —R¹⁰NR⁷R⁸,—OR¹⁰NR⁷R⁸, nitro, and cyano, wherein a is 0, 1 or 2; R⁶ is selectedfrom the group consisting of H, C₁₋₈alkyl, C₁₋₈alkoxy and C₂₋₈alkenyl;each R⁷ and R⁸ is the same or different and is independently selectedfrom the group consisting of H, C₁₋₈alkyl, C₂₋₈alkenyl and C₃₋₈alkynyl;R⁹ is selected from the group consisting of H, C₁₋₈alkyl and —NR⁷R⁸; andR¹⁰ is C₁₋₈alkyl. As will be appreciated by those skilled in the art,the number of possible substituents on the aryl ring will depend uponthe size of ring. For example, when the aryl ring is phenyl, the arylring may have up to 5 substituents selected from the foregoing list. Oneskilled in the art will readily be able to determine the maximum numberof possible substituents for a 1-naphthyl or 2-naphthyl ring. Apreferred aryl ring according to formula (II) is phenyl, which may besubstituted as described above.

The term “heterocycle” refers to a monocyclic saturated or unsaturatednon-aromatic carbocyclic rings and fused bicyclic non-aromaticcarbocyclic rings, having the specified number of members in the ringand containing 1, 2 or 3 heteroatoms selected from N, O and S. Examplesof particular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane,thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. The term “heterocycle” also refers tosubstituted heterocycles wherein the heterocyclic ring bears one or moresubstituents selected from the group consisting of halo, —OH, C₁₋₈alkyl,C₂₋₈alkenyl, C₁₋₈alkoxy, C₂₋₈alkenyloxy, S(O)_(a)R⁶, —NR⁷R⁸, —COR⁶,—COOR⁶, —R¹⁰COOR⁶, —OR¹⁰COOR⁶, —CONR⁷R⁸, —OC(O)R⁹, —R¹⁰NR⁷R⁸,—OR¹⁰NR⁷R⁸, nitro, and cyano, wherein a is 0, 1 or 2; R⁶ is selectedfrom the group consisting of H, C₁₋₈alkyl, C₁₋₈alkoxy and C₂₋₈alkenyl;each R⁷ and R⁸ is the same or different and is independently selectedfrom the group consisting of H, C₁₋₈alkyl, C₂₋₈alkenyl and C₃₋₈alkynyl;and R⁹ is selected from the group consisting of H, C₁₋₈alkyl and —NR⁷R⁸;and R¹⁰ is C₁₋₈alkyl. As will be appreciated by those skilled in theart, the number of possible substituents on the heterocyclic ring willdepend upon the size of ring. There are no restrictions on the positionsof the optional substituents in the heterocycles. Thus, the termencompasses rings having a substituent attached to the ring through aheteroatom. One skilled in the art will readily be able to determine themaximum number and locations of possible substituents for any givenheterocycle. A preferred heterocycle according to the invention ispiperidine, which may be substituted as described above.

The term “heteroaryl” refers to aromatic monocyclic heterocyclic ringsand aromatic fused bicyclic rings having the specified number of membersin the ring, having at least one aromatic ring and containing 1, 2 or 3heteroatoms selected from N, O and S. Examples of particular heteroarylgroups include, but are not limited to, furan, thiophene, pyrrole,imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole,oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine,pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole,and indazole. The term “heteroaryl” also refers to substitutedheteroaryls wherein the heteroaryl ring bears one or more substituentsselected from the group consisting of halo, —OH, C₁₋₈alkyl, C₂₋₈alkenyl,C₁₋₈alkoxy, C₂₋₈alkenyloxy, S(O)_(a)R⁶, —NR⁷R⁸, —COR⁶, —COOR⁶,—R¹⁰COOR⁶, —OR¹⁰COOR⁶, —CONR⁷R⁸, —OC(O)R⁹, —R¹⁰NR⁷R⁸, —OR¹⁰NR⁷R⁸, nitro,and cyano, wherein a is 0, 1 or 2; R⁶ is selected from the groupconsisting of H, C₁₋₈alkyl, C₁₋₈alkoxy and C₂₋₈alkenyl; each R⁷ and R⁸is the same or different and is independently selected from the groupconsisting of H, C₁₋₈alkyl, C₂₋₈alkenyl and C₃₋₈alkynyl; and R⁹ isselected from the group consisting of H, C₁₋₈alkyl and —NR⁷R⁸; and R¹⁰is C₁₋₈alkyl. As will be appreciated by those skilled in the art, thenumber of possible substituents on the heteroaryl ring will depend uponthe size of ring. There are no restrictions on the positions of theoptional substituents in heteroaryls. Thus, the term encompasses ringshaving a substituent attached to the ring through a heteroatom. Oneskilled in the art will readily be able to determine the maximum numberand locations of possible substituents for any given heteroaryl. Apreferred heteroaryl according to the invention is pyridine, which maybe substituted as described above.

The term “protecting group” refers to suitable protecting groups usefulfor the synthesis of compounds of formula (I) wherein X is OH. Suitableprotecting groups are known to those skilled in the art and aredescribed in Protecting Groups in Organic Synthesis, 3^(rd) Edition,Greene, T. W.; Wuts, P. G. M. Eds.; John Wiley & Sons: NY, 1999.Examples of preferred protecting groups include but are not limited tomethyl, ethyl, benzyl, substituted benzyl, and tert-butyl. In oneembodiment the protecting group is methyl.

Example 16 of PCT/US01/27622 (Smith Kline Beecham plc) has the followingstructure:

Compounds of formula II can be made according to any suitable method oforganic chemistry. One method given in the specification is a solidphase synthesis process as depicted in Scheme 2.

-   -   wherein X⁰ is —O— or —NH—, SP is solid phase, R¹⁵ is H or a        protecting group, and all other variables are as defined above        in connection with the description of compounds of formula (II).

In general, the reaction proceeds by a) reacting a solid phase-boundamine (where X in the compound of formula (II) is NH₂) or alcohol (whereX in the compound of formula (II) is OH) with a compound of formula (x)and a coupling agent to produce a solid phase-bound compound of formula(xi); b) in the embodiment wherein R¹⁵ is a protecting group,deprotecting the solid phase bound compound to prepare the compound offormula (xi); c) alkylating the solid phase-bound compound of formula(xi) with an alcohol of formula (xii) to produce a solid phase-boundcompound of formula (xiii); d) reacting the solid-phase-bound compoundof formula (xiii) with a compound of formula (xiv) to produce thesolid-phase bound compound of formula (xv); and e) reacting the solidphase-bound compound of formula (xv) with a compound of formula (xvi)under reductive amination conditions to produce the solid phase-boundcompound of formula (II). The process may optionally further comprisethe step of cleaving the solid phase-bound compound of formula (II) fromthe solid phase using conventional techniques such as treatment withmild acid.

Compounds of formula (II) are commercially available or can be preparedusing conventional techniques such as those described in European PatentNo. 303,742.

Compounds of formula (II) are commercially available or can be preparedusing conventional techniques such as those described in European PatentNo. 303,742.

Compounds of formula (III) are described in U.S. Provisional ApplicationNos. 09/368,427, 60/368,425 and 60/368,426, each filed Mar. 27, 2002:

wherein:

-   -   X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro,        cyano, —COOR¹⁰, —COR¹³, —OCOR¹³, —CONR¹⁴R¹⁵, —N(R¹⁷)COR¹³,        —N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵,        —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁷)SO₂R¹⁶, and a 5 or 6-membered        heterocyclic group;    -   or X and an adjacent R³, taken together with the atoms to which        they are bonded, form an alkylenedioxy moiety;    -   Z is CH, CR³ or N, wherein when Z is CH or CR³, k is 0-4 and t        is 0 or 1, and when Z is N, k is 0-3 and t is 0;    -   Y is selected from —O—, —S—, —N(R¹⁰)—, and —C(R⁴)(R⁵)—;    -   W¹ is selected from C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl and Het,        wherein said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, Ar and Het are        optionally unsubstituted or substituted with one or more groups        independently selected from halo, cyano, nitro, C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰,        —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR′″ R¹², —C₀-C₆        alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆        alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆        alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally        unsubstituted or substituted by one or more halo substituents;    -   W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆        alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹²,        —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆        alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents,        and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said        —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl are optionally unsubstituted or substituted with one        or more groups independently selected from halo, cyano, nitro,        C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰,        —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆        alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆        alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆        alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally        unsubstituted or substituted by one or more halo substituents;    -   W³ is selected from the group consisting of: H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-C₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆        alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   Q is selected from C₃-C₈ cycloalkyl, Ar and Het; wherein said        C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or        substituted with one or more groups independently selected from        halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³,        —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆        alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said        C₁-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   p is 0-8;    -   n is 2-8;    -   m is 0 or 1;    -   q is 0 or 1;    -   t is 0 or 1;    -   each R¹ and R² are independently selected from H, halo, C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het, —C₁-C₆        alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R²        together with the carbon to which they are attached form a 3-5        membered carbocyclic or heterocyclic ring, wherein said        heterocyclic ring contains one, or more heteroatoms selected        from N, O, and S, where any of said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   each R³ is the same or different and is independently selected        from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆        alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇        cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-S₂R¹⁰, —C₀-C₆ alkyl-SOR³, —C₀-C₆        alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³,        —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and        —C₀-C₆ alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   each R⁴ and R⁵ is independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R⁶ and R⁷ are each independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R⁸ and R⁹ are each independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R¹⁰ is selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆        alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆        alkyl-C₃-C₇ cycloalkyl;    -   each R¹¹ and each R¹² are independently selected from H, C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆        alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹¹ and R¹²        together with the nitrogen to which they are attached form a 4-7        membered heterocyclic ring which optionally contains one or more        additional heteroatoms selected from N, O, and S;    -   R¹³ is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het,        —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆        alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-S(O),        —C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar, —C₀-C₆        alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O)_(x)—C₃-C₇ cycloalkyl,        —C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₆        alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆        alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-Ar, —C₀-C₆        alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or        2, or R¹⁴ and R¹⁵, together with the nitrogen to which they are        attached, form a 4-7 membered heterocyclic ring which optionally        contains one or more additional heteroatoms selected from N, O,        and S, wherein said C₁-C₆ alkyl is optionally substituted by one        or more of the substituents independently selected from the        group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl),        —N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),        unsubstituted —OC₁-C₆ alkyl, —CO₂H, —CO₂ (unsubstituted C₁-C₆        alkyl), —CONH₂, —CONH(unsubstituted C₁-C₆ alkyl),        —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),        —SO₃H, —SO₂NH₂, —SO₂NH(unsubstituted C₁-C₆ alkyl) and        —SO₂N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl);    -   R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and

R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het;

or a pharmaceutically acceptable salt or solvate thereof.

Compounds of formula (IV) are described in U.S. Provisional ApplicationNo. 60/368,415, filed Mar. 27, 2002:

wherein:

-   -   X is CH or N;    -   Y is N(R¹⁰), O, or S, wherein t is 0 or 1 when Y is N(R¹⁰) or 0,        and t is 0 when Y is S;    -   U is selected from halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro, cyano, —COOR¹⁰,        —COR¹³, —OCOR¹³, —CONR¹⁴R⁵, —N(R¹⁴)COR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵,        —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁴)SO₂R¹⁶, and a 5 or 6-membered        heterocyclic group;    -   A is a phenyl fused ring moiety or a pyridyl fused ring moiety,        wherein when A is a phenyl ring moiety, k is 0-3 and t is 0 or 1        and when A is a pyridyl ring moiety, k is 0-2 and t is 0;    -   W¹ is selected from C₃-C₈ cycloalkyl, aryl and Het, wherein said        C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or        substituted with one or more groups independently selected from        halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₁-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³,        —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆        alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR³, where said        C₁-C₆ alkyl, is optionally unsubstituted or substituted by one        or more halo substituents;    -   W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR′″ R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³,        —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆        alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents,        and wherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said        —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl are optionally unsubstituted or substituted with one        or more groups independently selected from halo, cyano, nitro,        C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰,        —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆        alkyl-COR¹³, —C₀-C₆ alkyl-NR²¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆        alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆        alkyl-NR¹¹COR¹³, where said —C₁-C₆ alkyl, is optionally        unsubstituted or substituted by one or more halo substituents;    -   W³ is selected from the group consisting of: H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆        alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆        alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹², —C₀-C₆        alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆        alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   Q is selected from C₃-C₈ cycloalkyl, Ar and Het; wherein said        C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or        substituted with one or more groups independently selected from        halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³,        —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆        alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said        C₁-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   p is 0-8;    -   n is 2-8;    -   m is 0 or 1;    -   q is 0 or 1;    -   t is 0 or 1;    -   each R¹ and R² are independently selected from H, halo, C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het, —C₁-C₆        alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R²        together with the carbon to which they are attached form a 3-5        membered carbocyclic or heterocyclic ring, wherein said        heterocyclic ring contains one, or more heteroatoms selected        from N, O, and S, where said C₁-C₆ alkyl is optionally        unsubstituted or substituted by one or more halo substituents;    -   each R³ is the same or different and is independently selected        from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆        alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇        cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆        alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹²,        —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆        alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³,        —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆        alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆        alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, wherein said        C₀-C₆ alkyl is optionally unsubstituted or substituted by one or        more halo substituents;    -   each R⁴ and R⁵ is independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R⁶ and R⁷ are each independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R⁸ and R⁹ are each independently selected from H, halo, C₁-C₆        alkyl, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R¹⁰ is selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆        alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆        alkyl-C₃-C₇ cycloalkyl;    -   each R¹¹ and each R¹² are independently selected from H, C₁-C₆        alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆        alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹¹ and R¹²        together with the nitrogen to which they are attached form a 4-7        membered heterocyclic ring which optionally contains one or more        additional heteroatoms selected from N, O, and S;    -   R¹³ is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,        —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇        cycloalkyl;    -   R¹⁴ and R¹⁵ are each independently selected from H, C₁-C₆ alkyl,        C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het,        —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆        alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇ cycloalkyl, —C₀-C₆        alkyl-S(O)_(x)—C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar, —C₀-C₆        alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O)_(x)—C₃-C₇ cycloalkyl,        —C₀-C₆ alkyl-NH—Ar, —C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH—C₃-C₇        cycloalkyl, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄        alkyl)-Het, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆        alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl,        where x is 0, 1 or 2, or R¹⁴ and R¹⁵, together with the nitrogen        to which they are attached, form a 4-7 membered heterocyclic        ring which optionally contains one or more additional        heteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl        is optionally substituted by one or more of the substituents        independently selected from the group halo, —OH, —SH, —NH₂,        —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆        alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl,        —CO₂H, —CO₂ (unsubstituted C₁-C₆ alkyl), —CONH₂,        —CONH(unsubstituted C₁-C₆ alkyl), —CON(unsubstituted C₁-C₆        alkyl)(unsubstituted C₁-C₆ alkyl), —SO₃H, —SO₂NH₂,        —SO₂NH(unsubstituted C₁-C₆ alkyl) and —SO₂N(unsubstituted C₁-C₆        alkyl)(unsubstituted C₁-C₆ alkyl);    -   R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and    -   R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het;    -   or a pharmaceutically acceptable salt or solvate thereof.

Unless otherwise provided, each alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, aryl or Het (including any 3-5-membered, 4-7-membered or5-7-membered carbocyclic or heterocyclic rings or ring moieties) in thecompounds of formula (III) and (IV) is independently unsubstituted orsubstituted with one ore more substituents defined hereinbelow.

In the compounds of formula (IV), group A is defined as a phenyl or apyridyl fused ring moiety and is exemplified by the following:

Group A fused ring moiety:

As used to define the compounds of formulas (II) or (IV), the term“alkyl” represents a straight- or branched-chain saturated hydrocarbon,containing 1 to 10 carbon atoms, unless otherwise provided, which may beunsubstituted or substituted by one or more of the substituentsdescribed below. Exemplary alkyls include, but are not limited to methyl(Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, neopentyl and hexyl and structural isomers thereof. Any“alkyl” herein may be optionally substituted by one or more of thesubstituents independently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, and—CO₂H.

When combined with another substituent term as used to define thecompounds of formulas (III) or (IV) (e.g., aryl or cycloalkyl as in-alkyl-Ar or -alkyl-cycloalkyl), the “alkyl” term therein refers to analkylene moiety, that is, an unsubstituted divalent straight- orbranched-chain saturated hydrocarbon moiety, containing 1 to 10 carbonatoms, unless otherwise provided. For example, the term “—C₀-C₆alkyl-Ar”, where C is 1-6 is intended to mean the radical -alkyl-aryl(e.g., —CH₂-aryl or —CH(CH₃)-aryl) and is represented by the bondingarrangement present in a benzyl group. The term “C₀ alkyl” in a moiety,such as —C₀-C₆ alkyl-Ar or —O—(CO—C₆ alkyl)-Ar, provides for noalkyl/alkylene group being present in the moiety. Thus, when C is zero,—C₀-C₆ alkyl-Ar is equivalent to —Ar and —O—(C₀-C₆ alkyl)-Ar isequivalent to —O—Ar.

As used to define the compounds of formulas (III) or (IV), the term“alkenyl” represents a straight- or branched-chain hydrocarbon,containing 2 to 10 carbon atoms, unless otherwise provided, and one ormore carbon-carbon double bonds. Alkenyl groups may be unsubstituted orsubstituted by one or more of the substituents described below.Exemplary alkenyls include, but are not limited ethenyl, 1-propenyl,2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, pentenyl andhexenyl and structural isomers thereof. Both cis (Z) and trans (E)isomers of each double bond that may be present in the compounds offormula (III) or (IV) are included within the scope of this definition.Any “alkenyl” herein may be optionally substituted by one or more of thesubstituents independently selected from the group halo, —OH, —SH, —NH₂,—NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, and—CO₂H.

As used to define the compounds of formulas (III) or (IV), the term“alkynyl” represents a straight- or branched-chain hydrocarbon,containing 2 to 10 carbon atoms, unless otherwise provided, and one ormore carbon-carbon triple bonds and, optionally, one or morecarbon-carbon double bonds. Both cis (Z) and trans (E) isomers of eachdouble bond that may be present in the compounds of formula (III) or(IV) are included within the scope of this definition. Exemplaryalkynyls include, but are not limited ethynyl, propynyl (propargyl,isopropynyl), 1-butynyl, 2-butynyl, 3-butynyl, pentynyl and hexynyl andstructural isomers thereof. Any “alkynyl” herein may be optionallysubstituted by one or more of the substituents independently selectedfrom the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl),—N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl), unsubstituted—OC₁-C₆ alkyl, and —CO₂H.

As used to define the compounds of formulas (III) or (IV), when analkenyl or alkynyl group is a substituent on an oxygen, nitrogen orsulfur atom (e.g., as in oxy (—OR), thio (—SR), ester (—CO₂R or—C(O)SR), amino (—NRR) or amido (—CONRR) moieties and the like), it isunderstood that a double or triple bond of the alkenyl or alkynyl groupis not located on carbons that are α,β to the oxygen, nitrogen or sulfuratom. Compounds containing ene-amino or enol-type moieties (—NR—CR═CR—or —O—CR═CR—) are not intended to be included within the scope of thedefinition of the compounds of formula (III) or (IV).

As used to define the compounds of formulas (III) or (IV), the term“cycloalkyl” represents a non-aromatic monocyclic, bicyclic, ortricyclic hydrocarbon containing from 3 to 10 carbon atoms which may beunsubstituted or substituted by one or more of the substituentsdescribed below and may be saturated or partially unsaturated. Exemplarycycloalkyls include monocyclic rings having from 3-7, preferably 3-6,carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl andcycloheptyl. Any “cycloalkyl” herein may be optionally substituted byone or more of the substituents independently selected from the grouphalo, cyano, C₁-C₆ alkyl (which specifically includes C₁-C₆ haloalkyl,—C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl,oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆alkyl-NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H or unsubstituted C₁-C₆ alkyl.

As used to define the compounds of formulas (III) or (IV), the terms“Ar” or “aryl” is used interchangeably at all occurrences mean asubstituted or unsubstituted carbocyclic aromatic group, which may beoptionally fused to another carbocyclic aromatic group moiety or to acycloalkyl group moiety, which may be optionally substituted orunsubstituted. Examples of suitable Ar or aryl groups include phenyl,naphthyl indenyl, 1-oxo-1H-indenyl and tetrahydronaphthyl. Any “Ar”,“aryl” or “phenyl” herein may be optionally unsubstituted or substitutedby one or more of the substituents independently selected from the grouphalo, cyano, C₁-C₆ alkyl (which specifically includes C₁-C₆ haloalkyl,—C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl,—OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′,—C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂₋₇C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″, and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″are independently selected from H or unsubstituted C₁-C₆ alkyl.

As used to define the compounds of formulas (III) or (IV), the term“Het” means a stable 5- to 7-membered monocyclic, a stable 7- to10-membered bicyclic, or a stable 11- to 18-membered tricyclicheterocyclic ring group, all of which are saturated, unsaturated oraromatic, and consist of carbon atoms and from one to three heteroatomsselected from the group consisting of N, O and S, and which includesbicyclic and tricyclic rings containing one or more fused cycloalkyl,aryl (e.g., phenyl) or heteroaryl (aromatic Het) ring moieties. As usedherein the term “Het” is also intended to encompass heterocyclic groupscontaining nitrogen and/or sulfur where the nitrogen or sulfurheteroatoms are optionally oxidized or the nitrogen heteroatom isoptionally quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom that results in the creation of a stablestructure. Any “Het” herein may be optionally unsubstituted orsubstituted by one or more of the substituents independently selectedfrom the group halo, cyano, C₁-C₆ alkyl (which specifically includesC₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH, —C₀-C₆ alkyl-SH and —C₀-C₆alkyl-NR′R″), C₃-C₆ alkenyl, oxo, —OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆alkyl-COR′, —C₀-C₆ alkyl-CO₂R′, —C₀-C₆ alkyl-CONR′R″, —OC₀-C₆alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆ alkyl-C(═NR′)NR′R″ and —C₀-C₆alkyl-SO₂NR′R″, wherein each R′ and R″ are independently selected from Hor unsubstituted C₁-C₆ alkyl.

Examples of such heterocyclic groups include, but are not limited topiperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepanyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl,pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, 1,3-benzodioxolyl (e.g.,methylenedioxy-substituted phenyl), 1,4-benzodioxolyl, quinuclidinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzoxazolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl,dihydrobenzothienyl, dihydroindolyl, tetrazolyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, as well astriazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyridazinyl, pyrimidinyl and triazinyl which are availableby routine chemical synthesis and are stable.

Examples of the 4-7 membered heterocyclic rings useful in the compoundsof formula (III) or (IV), include, but are not limited to azetidinyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, azepanyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl,oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl,thiazolidinyl, thiazolinyl, thiazolyl, furyl, pyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, tetrazolyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl,thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl and triazinyl which are available by routinechemical synthesis and are stable. The 4-7 membered heterocyclic groupmay be optionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, oxo,—OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′,—C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″ and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H or unsubstituted C₁-C₆ alkyl.

Examples of 5 or 6 membered heterocyclic groups include, but are notlimited to piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl,oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl,thiazolinyl, thiazolyl, furyl, pyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, tetrazolyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl, as well as triazolyl,thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyridazinyl, pyrimidinyl and triazinyl which are available by routinechemical synthesis and are stable. The 5-6 membered heterocyclic groupmay be attached at any heteroatom or carbon atom that results in thecreation of a stable structure. The 5-6 membered heterocyclic group maybe optionally unsubstituted or substituted by one or more of thesubstituents independently selected from the group halo, cyano, C₁-C₆alkyl (which specifically includes C₁-C₆ haloalkyl, —C₀-C₆ alkyl-OH,—C₀-C₆ alkyl-SH and —C₀-C₆ alkyl-NR′R″), C₃-C₆ alkenyl, oxo,—OC₁-C₆alkyl, —OC₁-C₆ alkenyl, —C₀-C₆ alkyl-COR′, —C₀-C₆ alkyl-CO₂R′,—C₀-C₆ alkyl-CONR′R″, —OC₀-C₆ alkyl-CO₂H, —OC₂-C₆ alkyl-NR′R″, —C₀-C₆alkyl-C(═NR′)NR′R″ and —C₀-C₆ alkyl-SO₂NR′R″, wherein each R′ and R″ areindependently selected from H or unsubstituted C₁-C₆ alkyl.

In the compounds of formulas (III) and (IV), the terms “halogen” and“halo” represent chloro, fluoro, bromo or iodo substituents; “alkoxy” isintended to mean the radical —OR_(a), where R_(a) is an alkyl group,wherein alkyl is as defined above, provided that —O—C₁ alkyl may beoptionally substituted by one or more of the substituents independentlyselected from the group halo and —CO₂H. (exemplary alkoxy groups includemethoxy, ethoxy, propoxy, and the like); “phenoxy” is intended to meanthe radical —OR_(ar), where R_(ar) is a phenyl group; “acetoxy” isintended to mean the radical —O—C(═O)-methyl; “benzoyloxy” is intendedto mean the radical —O—C(═O)-phenyl; and “oxo” is intended to mean theketo diradical ═O, such as present on a pyrrolidin-2-one ring.

A method for the preparation of compounds of formula (III), comprisesthe steps of:

-   -   (a) reacting an alcohol having the formula: HY′—(CR⁴R⁵)_(n)-L,        where Y′ is —O—, —S—, —NH or protected —NH and L is a leaving        group, such as a halogen (iodide, bromide or chloride),        sulfonate (tosylate, mesylate, triflate, etc.) or is a group        that is converted to a leaving group (e.g., an alcohol), with an        alcohol having the formula:        where X is a protected carboxylic acid moiety, to form a        compound having the formula:    -   (b) reacting the compound formed in step (a) with a secondary        amine having the formula        to form a compound having the formula:    -   (c) converting the protected carboxylic acid moiety into a        desired amide moiety; and    -   (d) optionally oxidizing the compound formed in step (b) to the        N-oxide thereof.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting an acetylene having the formula:        R′O—(CR⁴R⁵)_(n-1)—C≡C—H, where R′ is a hydroxyl protecting        group, with a halogen-containing aromatic compound having the        formula        where X is a protected carboxylic acid moiety and Halo is bromo        or iodo, in the presence of a catalyst to form a compound having        the formula:    -   (b) reducing the compound formed in step (a) and converting the        protected hydroxyl group into a leaving group, L, such as a        halogen (iodide, bromide or chloride), sulfonate (tosylate,        mesylate, triflate, etc.) or is a group that is converted to a        leaving group (e.g., an alcohol), to form a compound having the        formula:    -   (c) reacting the compound formed in step (b) with an amine        having the formula:        to form a compound having the formula:        (d) converting the protected carboxylic acid moiety into a        desired amide moiety; and    -   (e) optionally oxidizing the compound formed in step (b) to the        N-oxide thereof.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting an alcohol having the formula: L′-(CR⁴R⁵)_(n)-L,        where L′ and L are leaving groups, which may be the same or        different, such as a halogen (iodide, bromide or chloride),        sulfonate (tosylate, mesylate, triflate, etc.) or is a group        that is converted to a leaving group (e.g., an alcohol), with a        compound having the formula:        where Y′ is —O—, —S—, or —NH— and X is defined as above or a        protected form thereof, to form a compound having the formula:    -   (b) reacting the compound formed in step (a) with a secondary        amine having the formula        to form a compound having the formula:    -   (c) removing any protecting groups; and    -   (d) optionally oxidizing the compound formed in step (b) or (c)        to the N-oxide thereof.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting a compound having the formula:        where Y′ is —O—, —S—, or —NH— and R′ is a suitable protecting        group for —OH, —SH, or —NH₂, with a hydrazide or azide to form a        heterocyclic-containing compound having the formula:    -   (b) optionally protecting the NH moiety of the heterocyclic        group with a protecting group, and removing the R′ protecting        group;    -   (c) reacting the compound formed in step (b) with a compound        having the formula: L′-(CR⁴R⁵)_(n)-L, where L′ and L are leaving        groups, which may be the same or different, such as a halogen        (iodide, bromide or chloride), sulfonate (tosylate, mesylate,        triflate, etc.) or is a group that is converted to a leaving        group (e.g., an alcohol), to form a compound having the formula:        where P is an optional protecting group or H;    -   (d) reacting the compound formed in step (c) with an amine        having the formula:        to form a compound having the structure:    -   (e) removing any protecting groups.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting an acetylene having the formula:        R′O—(CR⁴R⁵)_(n-1)—C≡C—H, where R′ is a hydroxyl protecting        group, with a halogen-containing aromatic compound having the        formula        where Halo is bromo or iodo, in the presence of a catalyst to        form a compound having the formula:    -   (b) reducing the compound formed in step (a) and converting the        protected hydroxyl group into a leaving group, L, such as a        halogen (iodide, bromide or chloride), sulfonate (tosylate,        mesylate, triflate, etc.) or is a group that is converted to a        leaving group (e.g., an alcohol) to form a compound having the        formula:    -   (c) reacting the compound formed in step (b) with an amine        having the formula:        to form a compound having the formula:    -   (d) removing any protecting groups; and    -   (e) optionally oxidizing the compound formed in step (c) or (d)        to the N-oxide thereof.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting an alcohol having the formula: HO—(CR⁴R⁵)_(n)-L,        where L is a leaving group, such as a halogen (iodide, bromide        or chloride), sulfonate (tosylate, mesylate, triflate, etc.) or        is a group that is converted to a leaving group (e.g., an        alcohol) with a phenol having the formula:        to form an aryl ether having the formula:    -   (b) reacting an amine having the formula        with and an aldehyde having the formula Q-CHO or a ketone to        form a secondary amine having the formula:    -   (c) reacting the ether formed in step (a) with the secondary        amine formed in step (b) to form a compound of this invention        having the formula:    -   (d) when R¹⁰ is other than H, optionally converting the compound        formed in step (c) to the compound of this invention, wherein        R¹⁰ is H.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting an alcohol having the formula: HO—(CR⁴R⁵)_(n)-L,        where L is a leaving group, such as a halogen (iodide, bromide        or chloride), sulfonate (tosylate, mesylate, triflate, etc.) or        is a group that is converted to a leaving group (e.g., an        alcohol), with an amine having the formula:        to form a tertiary amine having the formula:    -   (b) reacting the tertiary amine formed in step (a) with a phenol        having the formula:        to form a compound of this invention having the formula:    -   (c) when R¹⁰ is other than H, optionally converting the compound        formed in step (b) to the compound of this invention, wherein        R¹⁰ is H.

Another method for the preparation of compounds of formula (III),comprises the steps of:

-   -   (a) reacting an alcohol having the formula: HO—(CR⁴R⁵)_(n)-L,        where L is a leaving group, such as a halogen (iodide, bromide        or chloride) or sulfonate (tosylate, mesylate, triflate, etc.),        with a phenol having the formula:        to form an ether-alcohol having the formula:    -   (b) converting alcohol moiety of the ether-alcohol formed in        step (a) into L′, where L′ is a leaving group such as a halogen        (iodide, bromide or chloride), sulfonate (tosylate, mesylate,        triflate, etc.) or is a group that is converted to a leaving        group (e.g., an alcohol) and treating the resulting compound        with an amine having the formula:        to form a compound of this invention having the formula:    -   (c) when R¹⁰ is other than H, optionally converting the compound        formed in step (b) to the compound of this invention, wherein        R¹⁰ is H.

The method for the preparation of compounds of formula (IV), comprisesthe steps of:

-   -   (a) coupling an acetylene having the formula: with a phenol        having the formula:        where Halo is a halogen selected from iodo or bromo, in the        presence of a metal catalyst to form an aryl-alcohol having the        formula:    -   (b) converting alcohol moiety of the aryl-alcohol formed in        step (a) into L′, where L′ is a leaving group such as a halogen        (iodide, bromide or chloride), sulfonate (tosylate, mesylate,        triflate, etc.) or is a group that is converted to a leaving        group (e.g., an alcohol), and treating the resulting compound        with an amine having the formula:        to form the compound of formula (IV);    -   (c) optionally converting the compound of formula (IV) from        step (b) into another compound of formula (IV); and    -   (d) optionally oxidizing the compound formed in step (c) to the        N-oxide thereof.

Alternatively, the compounds of formula (IV) may be prepared by

-   -   (a) coupling an acetylene having the formula: with a phenol        having the formula:        where Halo is a halogen selected from iodo or bromo, in the        presence of a metal catalyst to form an aryl-alcohol having the        formula:    -   (b) converting alcohol moiety of the aryl-alcohol formed in        step (a) into L′, where L′ is a leaving group such as a halogen        (iodide, bromide or chloride) or a sulfonate (tosylate,        mesylate, triflate, etc.) and treating the resulting compound        with sodium azide, followed by hydrogenation in the presence of        a palladium catalyst to form a primary amine having the formula:    -   (c) treating the primary amine with a first aldehyde in the        presence of a reducing agent, to form a secondary amine and        treating the secondary amine with a second aldehyde in the        presence of a reducing agent to form the compound of formula        (IV);    -   (d) optionally converting the compound of formula (IV) from        step (b) into another compound of formula (IV); and    -   (e) optionally oxidizing the compound formed in step (b) or (c)        to the N-oxide thereof.

International Patent Application WO 01/41704 (Merck & Co., Inc.)discloses a compound of formula (V):

the use of compound (VI):

and related compounds alongside methods for their production asdescribed in International Patent Application WO97/28137 (Merck & Co.,Inc), along with methods for making them, as being useful as an agonistof LXR and their use in pharmaceutical formulations to reversecholesterol transport and treat atherosclerotic cardiovascular diseasesand related diseases.

Other LXR agonists may be identified by assays such as those describedin the above referenced patent applications, for example, the assaysdescribed in Examples 1 and 2 of PCT/US01/27622. Biotinylated LXRβprotein was incubated for 20-25 minutes at a concentration of 25 nM inassay buffer (50 mM KCl, 50 mM Tris-pH8, 0.1 mg/ml FAF-BSA, 10 mM DTT)with equimolar amounts of streptavidin-AlloPhycoCyanin (APC, MolecularProbes). At the same time, the biotinylated peptide comprising aminoacids 675-699 of SRC-1 (CPSSHSSLTERHKILHRLLQEGSPS-CONH2) (SEQ ID No. 2)at a concentration of 25 nM was incubated in assay buffer with a ½ molaramount of streptavidin-labelled Europium (Wallac) for 20-25 minutes.After the initial incubations are completed, a 10 molar excess (250 nM)of cold biotin was added to each of the solutions to block theunattached streptavidin reagents. After 20 min at room temp, thesolutions were mixed yielding a concentration of 12.5 nM for thedye-labelled LXRβ protein and SRC-1 peptide. 80 μL of theprotein/peptide mixture was added to each well of an assay platecontaining 20 μL of test compound. The final volume in each well was 0.1mL, and the concentration in the well for the dye-labelled protein andpeptide was 10 nM. The final test compound concentrations were between56 pM and 10 μM. The plates were incubated at room temp in the dark for4-12 hours and then counted on a Wallac Victor fluorescent plate reader.In this assay 1 μM 24(S), 25-epoxycholesterol gave a reading of 20000fluorescence units over a background reading of 10000 fluorescenceunits. The assay for LXRα was run according to the procedures describedabove using his-tagged LXRα ligand binding domain (amino acids 183-447of Genbank accession number U22662, with the 14^(th) amino acidcorrected to A from R).

The invention provides the use of a LXR agonist in the preparation of amedicament for the treatment and/or prophylaxis of diseases orconditions characterised by neuron degeneration, inflammation in theCNS, injury or impaired plasticity.

The invention also provides a method of treating or preventing diseasesor disorders characterised by neuron degeneration, inflammation in theCNS, injury or impaired plasticity which comprises administering to asubject in need thereof an effective non-toxic and pharmaceuticallyacceptable amount of a LXR agonist, such as compounds of formula (I),(II), (III), (IV), (V) and (VI) or a pharmaceutically acceptablederivative thereof.

Furthermore, the invention provides the use of a LXR agonist in thepreparation of a medicament for the promotion of growth and/or repair ofneurons in diseases or conditions characterised by neuron degeneration,inflammation in the CNS, injury or impaired plasticity which methodcomprises the administration of an effective, non-toxic andpharmaceutically acceptable amount of a LXR agonist, such as compoundsof formula (I), (II), (III), (IV), (V) and (VI) or a pharmaceuticallyacceptable derivative thereof.

The invention also provides a method for the promotion of growth and/orrepair of neurons in diseases or conditions characterised by neurondegeneration, inflammation in the CNS, injury or impaired plasticitywhich method comprises the administration of an effective, non-toxic andpharmaceutically acceptable amount of a LXR agonist, such as compoundsof formula (I), (II), (III), (IV), (V) and (VI) or a pharmaceuticallyacceptable derivative thereof.

Suitable diseases or conditions are those characterised by neurondegeneration.

Suitable diseases or conditions are those characterised by neuroninjury.

Suitable diseases or conditions are those characterised by impairedplasticity.

Suitable diseases or conditions are those characterised by inflammationin the CNS.

Particular diseases or conditions are characterised by neurondegeneration and inflammation, and thus benefiting from the growthand/or repair of neurons including stroke, Alzheimer's disease,fronto-temporal dementias (tauopathies), peripheral neuropathy,Parkinson's disease, dementia with Lewy bodies, Huntington's disease,amyotrophic lateral sclerosis and multiple sclerosis.

Diseases or conditions characterised by neuron degeneration and/orimpaired plasticity include psychiatric disorders such as schizophreniaand depression.

Particular diseases or conditions characterised by neuronal injuryinclude those conditions associated with brain and/or spinal cordinjury, including trauma.

Accordingly, the present invention also provides a pharmaceuticalcomposition for the promotion of growth and/or repair of neurons indiseases or conditions characterised by neuron degeneration,inflammation in the CNS, injury or impaired plasticity, whichcomposition comprises a LXR agonist and a pharmaceutically acceptablecarrier therefor.

Suitable pharmaceutically acceptable salts include salts of saltsderived from appropriate acids, such as acid addition salts, or bases.

Suitable pharmaceutically acceptable salts include metal salts, such asfor example aluminium, alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium andammonium or substituted ammonium salts, for example those with loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

Suitable acid addition salts include pharmaceutically acceptableinorganic salts such as the sulphate, nitrate, phosphate, borate,hydrochloride and hydrobromide and pharmaceutically acceptable organicacid addition salts such as acetate, tartrate, maleate, citrate,succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate anda-glycerophosphate.

The LXR agonists referred to herein are conveniently prepared accordingto the methods disclosed in the above mentioned patent publications inwhich they are disclosed.

The salts and/or solvates of the LXR agonists may be prepared andisolated according to conventional procedures for example thosedisclosed in the, above mentioned, patent publications.

In the above mentioned method the LXR agonist, may be administered perse or, preferably, as a pharmaceutical composition also comprising apharmaceutically acceptable carrier.

In the treatment of the invention, the LXR agonist mentioned herein isformulated and administered in accordance with the methods disclosed inthe above mentioned patent applications and patents.

As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will beadapted for oral administration, although compositions foradministration by other routes, such as by injection and percutaneousabsorption are also envisaged.

Particularly suitable compositions for oral administration are unitdosage forms such as tablets and capsules. Other fixed unit dosageforms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice, the carrier maycomprise a diluent, filler, disintegrant, wetting agent, lubricant,colourant, flavourant or other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose,starch, sodium starch glycollate, polyvinylpyrrolidone,polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate orsucrose.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

Compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending upon the method ofadministration.

Compositions may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

The compositions are formulated according to conventional methods, suchas those disclosed in standard reference texts, for example the Britishand US Pharmacopoeias, Remington's Pharmaceutical Sciences (MackPublishing Co.), Martindale The Extra Pharmacopoeia (London, ThePharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books).

One index of synaptic plasticity is increased synaptic transmission.This can be measured in cultured hippocampal neurons usingelectrophysiological recordings as described by Levine E S, Crozier R A,Black I B, Plummer M R. “Brain derived neurotrophic factor modulateshippocampal synaptic transmission by increasing N-methyl-D aspartic acidreceptor activity”, in Proc. Natl. Acad. Sci USA Vol 95 pp10235-10239(1998). Thus the neurons would be treated with the compound under testand then their synaptic transmission determined against a controlfollowing glutamate exposure.

No adverse toxicological effects are expected for the compositions ormethods of the invention in the above mentioned dosage ranges.

Although the central nervous system (CNS) accounts for <10% of totalbody mass, it contains roughly a quarter of all the unesterifiedcholesterol present in the body (29). Virtually all of the cholesterolpresent in the brain is derived from in situ biosynthesis. Theconversion of cholesterol to the LXR ligand 24(S)-hydroxycholesterol,which can cross the blood brain barrier (BBB) and enter the generalcirculation, represents an important mechanism for cholesterol flux outof the CNS (30-32). Importantly, the dysregulation of cholesterolbalance in the brain may be related to the onset of neurological disease(29). Cholesterol turnover across the brain is increased inneurodegenerative disorders such as Alzheimer's disease (AD) andNiemann-Pick Type C disease (33-34). Moreover, there is clinicalevidence that patients with elevated cholesterol levels have increasesusceptibility to AD (35, 36), and, conversely, that treatment with thestatin class of cholesterol-lowering drugs reduces the incidence of AD(37,38). Finally, the E2 and E4 isoforms of apoE, which transportscholesterol throughout the body, have been genetically linked to eithera decreased or increased risk of AD, respectively (39-41). Thus,understanding the mechanisms regulating cholesterol balance in the brainmay provide important insights into the etiology and treatment ofneurodegenerative disorders.

In recent years, great strides have been made in understanding thefunctions of LXRα and LXRβ in the regulation of cholesterol homeostasis.The LXRs regulate a number of genes involved in the biosynthesis,transport, and excretion of cholesterol and thus are likely to haveimportant implications in human diseases such as hypercholesterolemiaand atherosclerosis (25). However, the potential role that the LXRsmight play in the CNS has remained largely undefined. The brain is themost cholesterol-rich organ in the body, and dysregulation ofcholesterol homeostasis may influence the neurological disorders such asAD (35-38, 42, 43). The brain also produces virtually all of the body's24(S)-hydroxycholesterol, a cholesterol metabolite that serves as anefficacious agonist of both LXR subtypes (27, 28, 30). The expressionpatterns of cholesterol-24-hydroxylase, the enzyme that synthesizes24(S)-hydroxycholesterol, and LXRβ within the CNS are remarkably similar(26, 44). These observations suggest that the LXRs might serve asintegral components of a regulatory loop that modulates cholesterollevels and/or cholesterol partitioning in the brain.

In summary, in Examples 6-11 below, the inventors of the presentinvention demonstrate that LXR regulates a series of genes involved incholesterol homeostasis in the CNS, both in vitro and in vivo, as wellas cholesterol efflux from cultured astroglial cells. There is mountingevidence that cholesterol balance has an important impact on the onsetand/or progression of various CNS disorders, including AD. Thus, it isbelieved that LXR ligands and agonists will have utility in thetreatment of a range of CNS disorders caused by either trauma ordisease, including AD.

The following Examples are intended for illustration only and are notintended to limit the scope of the invention in any way; the presentinvention being defined by the appended claims.

EXAMPLES Example 12-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}-phenyl)aceticAcid

Argogel-MB-OH (6.0 g, 2.40 mmol, Argonaut Technologies) was treated witha solution of (3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetic acid(5.40 g, 19.2 mmol, Eur. Pat. Appl. (1987) Application: EP 87-30374219870428) in 50 mL of anhydrous dichloromethane followed bydicyclohexylcarbodiimide (4.16 g, 19.2 mmol) and 4-dimethylaminopyridine(2.50 g, 19.2 mmol). After rotating at room temperature for 15 hours,the resin was filtered, washed sequentially with dichloromethane (2×25mL), dimethylformamide (2×25 mL), dichloromethane (3×25 mL), methanol(3×25 mL), dichloromethane (3×25 mL) and diethyl ether (2×25 mL). Afterdrying under house vacuum overnight at 40° C., the resin was treatedwith 1.0 M tetrabutylammonium fluoride (24 mL, 23.4 mmol) intetrahydrofuran, and the mixture was rotated for 4 hours. The resin wasfiltered, washed sequentially with dichloromethane (2×25 mL),dimethylformamide (2×25 mL), dichloromethane (3×25 mL), methanol (3×25mL), and dichloromethane (3×25 mL) to give the deprotected phenol. Thedry resin was treated with 90 mL of anhydrous toluene followed bytriphenylphosphine (15.8 g, 60.0 mmol) and 3-bromo-1-propanol (8.4 g,60.0 mmol). Upon cooling to 0° C., diisopropyl azodicarboxylate (12.1 g,60.0 mmol) in 20 mL of anhydrous toluene was added in a dropwisefashion. The reaction was allowed to warm to room temperature andstirred for 15 hours. The resin was filtered, washed sequentially withdichloromethane (2×50 mL), dimethylformamide (2×50 mL), dichloromethane(3×50 mL), methanol (2×50 mL) and dichloromethane (3×50 mL), and driedunder house vacuum. The bromide functionalized resin was treated with asolution of diphenethylamine (25.0 g, 127 mmol) in 60 mL of anhydrousdimethylsulfoxide, and the reaction was rotated for 15 hours. The resinwas filtered, washed sequentially with dichloromethane (2×50 mL),dimethylformamide (2×50 mL), dichloromethane (3×50 mL), methanol (3×50mL) and dichloromethane (3×50 mL), and dried under house vacuum at 40°C. The secondary amine resin (5.75 g, 2.0 mmol) was treated with asolution of 2-chloro-3-trifluoromethylbenzaldehyde (8.32 g, 40.0 mmol)in 80 mL of 8% acetic acid in dimethylformamide. Solid sodiumtriacetoxyborohydride (8.5 g, 40.0 mmol) was added, and the reaction wasrotated for 15 hours. The resin was filtered, washed sequentially withdichloromethane (2×50 mL), dimethylformamide (2×50 mL), dichloromethane(3×50 mL), methanol (3×50 mL) and dichloromethane (3×50 mL), and driedunder house vacuum overnight at 50° C. The resin-bound product wastreated with 30 mL of trifluoroacetic acid/dichloromethane (15/85) for15 minutes, and the filtrate was collected. The cleavage procedure wasrepeated again, and the combined filtrates were concentrated underreduced pressure. The crude product was purified by preparative thinlayer chromatography (silica gel, 1 mm plates, Merck 20×20 cm silica gel60 F₂₅₄) eluting with methanol:dichloromethane (3:97) to give 7.0 mg ofthe title compound (5% yield based on theoretical loading of secondaryamine resin) of a viscous oil: ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (d, 1H,J=7.6), 7.23-7.10 (m, 12H), 6.85 (t, 2H, J=8.1), 6.63 (s, 1H), 6.61 (s,1H), 4.11 (t, 1H, J=7.8), 3.75 (s, 2H), 3.63 (t, 2H, J=6.0), 3.59 (s,2H), 2.12 (d, 2H, J=7.8), 2.67 (t, 2H, J=6.6), 1.81 (tt, 2H, J=6.2); MS(ESP+) m/e 582 (MH⁺); TLC (EtOAc:hexanes/1:1) R_(f)=0.58.

Example 2N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-benzenesulfonamide(T0901317)

12.1 Preparation of N-trifluoroethylaniline Derivative.

To a suspension of4-[2,2,2-triflouro-1-hydroxy-1-(trifluoromethyl)ethyl]aniline (9.07 g,35.0 mmol) in CH2CL2 (100 ml) was added to solution of trifluoroaceticanhydride (5.7 ml, 40.2 mmol) in CH2Cl2 (50 ml) dropwise at roomtemperature. The solution was stirred for 3 hours, the solution clearedand TLC indicated that the reaction was completed. The reaction mixturewas washed with water, aqueous NaHCO3, and brine. The organic layer wasdrawn off, dried over MgSO4, filtered and concentrated to give 12.1 g ofthe intermediate trifluoroacetanitrilide (12.1a). The intermediate 12.1awas taken up in the THF (50 ml) and treated with LiAlH4 (4.00 g, 106mmol) at refklux for 10 hours. The reaction was quenched sequentiallyadding 4 ml of water, 4 ml of 15% NaOH and 12 ml of water. The resultingsuspension was stirred for an additional 30 minutes, filtered through acelite pad, which was then rinsed with THF. The combined filtrate andrinse was concentrated under reduced pressure. The residue was taken upin EtOAc, washed with Brine, dried over MgSO4, filtered andconcentrated. The resulting crude product was purified by chromatographyon SiO2 (4:1 hexane:EtOAc as eluant) to provide 11.og (92%) of the titlecompound (12.1b).

¹H NMR (CDCl₃): δ 7.52 (J=8.6 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 4.10 (bs,1H), 3.80 (q, J=8.5 Hz, 2H), 3.31 (bs, 1H). MS (ES+): 342 (M+H, 100).

12.2 Sulfonylation of 12.1b

A sample of 12.1b from above (1.87 g, 5.48 mmol) was treated withbenzenesulfonylchloride (1.18 g, 6.68 mmol) in pyridine (10 ml) at roomtemperature for 10 days. The reaction mixture as diluted with EtOAc,washed with aqueous NaHCO3, and brine. The organic layer was dried overMgSO4, filtered and concentrated. The crude product was purified bychromatography on SiO2 (4:1 hexane:EtOAc as eluant) to provide 1.65 g(62%) of compound 12.

¹H NMR (CDCl₃): δ 7.78 (J=8.8 Hz, 2H), 7.61 (t, J=7.6 Hz, 1H), 7.58 (d,J=7.6 Hz, 2H), 7.46 (t, J=Hz, 2H), 4.24 (q, J=8.2 Hz, 2H), 3.41 (s, 1H).MS (ES−): 480 (M−H, 100). Anal. Calcd. for C₁₇H₁₂F₉NO₃S:C, 42.42; H,2.51; N, 2.91; S, 6.66. Found: C, 42.70; H, 2.55; N, 2.84; S, 6.61.

Example 3(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)aceticAcid Methyl Ester

a) Toluene-4-sulfonic acid-(S)-3-hydroxy-butyl Ester

To a stirring solution of (S)-1,3-butanediol (1.0 g, 0.01 mmol) andtriethylamine (1.39 g, 0.014 mmol) in dichloromethane (10 mL) at −20° C.was added dropwise p-toluenesulfonyl chloride and the mixture wasstirred for 2 h. The reaction mixture was then warmed to RT and stirredovernight. The reaction mixture was poured into cold H₂O (20 mL), andextracted three times with dichloromethane. The organic extracts werethen washed with brine. The organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo to give 2.6 g (96% yield) of titlecompound as an oil. MS(ESI) 244.8(M⁺). The crude tosylate was usedwithout further purification.

b)(S)-4-[N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethyl)amino]-butan-2-ol

To a stirring solution ofN-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl)amine (160 mg, 0.409mmol) and toluene-4-sulfonic acid-(S)-3-hydroxy-butyl ester (100 mg,0.409 mmol) in acetonitrile (5 mL) was added solid K₂CO₃ (170 mg, 1.23mmol) and NaI (184 mg 1.23 mol). The reaction mixture was heated toreflux and stirred overnight. The mixture was cooled to RT, filtered,and the filtrate was concentrated. The crude product was purified bypreparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H₂O, UV detection at 254 nm) to give 110 mg (58% yield) of the titlecompound as an oil. MS(ESI) 462.0(M+H⁺).

c)(R)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)aceticAcid Methyl Ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester(36 mg, 0.217 mmol) in anhydrous toluene (5 mL) was added(S)₄[N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl)amino]-butan-2-ol(100 mg, 0.217 mmol). Polymer bound triphenylphosphine (115 mg, 0.346mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture wasstirred for 15 minutes. The reaction mixture was then cooled to 0° C.and diisopropylazodicarboxylate (54 mg, 0.269 mmol) was added in adropwise fashion. The reaction mixture was stirred overnight at roomtemperature. The reaction mixture was next filtered and the remainingsolid was washed with toluene. The filtrate was concentrated and thecrude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30mm, 25 mL/min, A: acetonitrile B: H2O, A: 85 to 100% during 10 min, UVdetection at 254 nm) to give 56 mg (42% yield) of title compound as aviscous oil. MS(ESI) 610.0(M⁺).

Example 4(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine

a) 5-(3-Benzyloxy-benzyl)-1,2,3,4-tetrazole

To a stirring solution of 3-benzyloxyphenylacetonitrile (2.0 g, 8.95mmol) in toluene (17 ml) was added trimethylsilylazide (2.37 g, 17.9mmol) and di-n-butyltin oxide (0.22 g, 0.9 mmol). The mixture was heatedat 110° C. for 48 h, and was concentrated. The reaction mixture wasdissolved in ethyl acetate (100 ml) and washed two times with 10%aqueous sodium bicarbonate. The basic extracts were acidified to pH<2with conc. HCl, and the aqueous layer was extracted with ethyl acetate.The combined organic layers were dried over sodium sulfate, filtered,and concentrated. The crude product (2.0 g, 89%) was used in the nextstep without further purification. MS (ESI) 267.0 (M+H⁺).

b) 5-(3-Benzyloxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole

Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-

To a stirring solution of 3-(3-benzyloxy-benzyl)-1,2,3,4-tetrazole (2.12g, 7.96 mmol) in DMF (40 ml) at 0° C. was added NaH (0.38 g, 9.55 mmol).To this mixture was added chloromethyl ethyl ether (0.81 ml, 8.75 mmol),and the solution was stirred at RT overnight. The reaction mixture waspoured into water (120 ml) and extracted three times with ethyl acetate.The ethyl acetate extracts were dried over Na₂SO₄, filtered, andconcentrated. The crude mixture was subjected to column chromatography(silica gel, ethyl acetate/hexane) to provide the title compounds as amixture of regioisomers as a light yellow oil (1.39 g, 55%). MS (ESI)324.8 (M+).

c) 5-(3-Hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole

Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-

To a stirring solution of5-(3-benzyloxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole (mixture ofregioisomers, 0.23 g, 0.71 mmol) in MeOH (5 ml) was added palladium oncarbon (20 mg). The mixture was stirred for 7 h under H₂ atmosphere,filtered, and concentrated. The crude phenol was purified by preparativeHPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H₂O, UVdetection at 254 nm) to afford the desired phenol as a clear oil (0.14g, 84%). MS (ESI) 235.0 (M+H⁺).

d) 5-[3-(3-Bromo-propoxy)-benzyl]-(ethoxymethyl)-1,2,3,4-tetrazole

Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-

A solution of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole(mixture of regioisomers, 132 mg, 0.56 mmol) in anhydrous toluene (5 ml)was treated with 3-bromo-propanol (117 mg, 0.84 mmol). Polymer boundtriphenylphosphine (0.56 mg, 1.7 mmol, 3 mmol/g, Fluka Chemie) was thenadded, and the mixture stirred for 15 minutes. The reaction mixture wasthen cooled to 0° C. and diisopropylazodicarboxylate (166 ul, 0.84 mmol)was added dropwise. The reaction mixture was stirred at RT overnight,filtered, and the filtrate was concentrated in vacuo to give 200 mg(100% yield) of a 1:1 mixture of the title compounds as a yellow oil. MS(ES) 356.8 (M+2H⁺).

e)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine

Mixture of Regioisomers for Ethoxymethyl Include 1- and 2-

A solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine(mixture of regioisomers, 0.2 g, 0.56 mmol) and(2,2-diphenylethyl)-(2-chloro-3-trifluoromethyl)amine (0.43 g, 1.12mmol) in acetonitrile (10 ml) was treated with solid potassium carbonate(0.23 g, 1.7 mmol) and NaI (0.25 g, 1.7 mmol). The reaction was heatedat reflux and stirred overnight. The mixture was cooled to RT, filtered,and concentrated. The crude product was purified by preparative HPLC(TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: water, WVdetection at 254 nm) to give 125 mg (33% yield) of the title compound asa viscous oil. MS (ESI) 664.2 (M⁺).

f)(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-(3-[3-(1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl)-amine

To a stirring solution of(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine(mixture of regioisomers, 125 mg, 0.19 mmol) in dichloromethane (11 ml)was added triethylsilane (116 mg, 1.08 mmol). The reaction mixture wastreated with TFA (3 ml) and then stirred overnight. Solvent was removedand the residue was purified by preparative HPLC (TMC CombiPrep PDS,75×30 mm, 25 mL/min, acetonitrile:water, UV detection at 254 nm) toafford 50 mg (44%) the title compound as a yellow oil. MS (ESI)607.0(M+H⁺).

Example 5(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)-acetamide

a) (S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine

To a solution of (S)-2-phenyl propylamine (0.5 g, 3.7 mmol) in drydichloromethane was added acetic acid followed by2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodiumtriacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture wasstirred for 1.5 h at RT water was added to quench the reaction. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The crude mixture was purified by columnchromatograph (Ethyl acetate:Hexane/25:75) to give the title compound asan oil (0.55 g, 45%). MS (ESI) 327.6 (M+H)⁺.

b)(S)-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticAcid Methyl Ester

A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (0.55g, 1.5 mmol) and(S)-(2-Chloro-3-trifluoromethyl-benzyl)(2-phenyl-propyl)-amine (0.55 g,1.6 mmol) in acetonitrile (10 ml) was treated with solid potassiumcarbonate (0.4 g, 2.4 mmol). The reaction was heated to reflux andstirred for 48 h. Upon cooling to RT, the reaction was filtered througha pad of celite, washed with ethyl acetate, and the filtrate wasconcentrated in vacuo. The crude product was purified by columnchromatograph (Ethyl acetate:Hexane/20:80) to give the title compound asan oil (0.6 g, 67%). MS (ESI) 534.6 (M+H)⁺.

c)(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticAcid

A solution of(S)-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid methyl ester (0.6 g, 1.1 mmol) in THF (9 ml) and water (6 ml) wastreated with aqueous LiOH (1.0 N, 1.0 ml, 1.0 mmol). After stirring atRT for 2 h, additional LiOH (11.0 ml, 1.0 mmol) was added and stirringwas continued for 2 h. The reaction was neutralized with acetic acid andpoured into water and ethyl acetate. The layers were separated and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated in vacuo. The crude mixture was purified by HPLC to givethe title compound as an oil (0.4 g, 75%). MS (ESI) 520.2 (M+H)⁺.

d)(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticAcid Hydrochloride Salt

To a solution of the(S)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid in ethyl ether was added HCl in diethyl ether (1.0M). Thesuspension was filtered and dried to give the title compound as a whitesolid (99%). NMR(400 MHz, CD₃OD) δ: 8.0 (d, J=4.0 Hz, 1H), 7.9 (d, J=4.0Hz, 1H), 7.7-7.3 (m, 7H), 7.1 (d, J=8.0 Hz, 1H), 6.8 (m, 2H), 4.1-3.4(m, 11H), 2.3 (m, 2H), 1.5 (d, J=4.0 Hz, 3H).

(e)(S)-2-(3-{3-[[2-Chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)-acetamide

To a solution(S)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2-phenyl-propyl)amino]propoxy}-phenyl)aceticacid hydrochloride salt (50 mg, 0.1 mmol) in dichloromethane,1,2-dichloroethane (EDC, 19.2 mg, 0.1 mmol), 1-hydroxybenzotriazolehydrate (HOBT, 13.6 mg, 0.1 mmol), triethylamine (Et₃N, 14 μl, 0.1 mmol)and ammonia (1.0M in dioxane, 0.24 ml) were added. After the resultingmixture was stirred at room temperature for over night it was washedwith 0.1N HCl, saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄ and concentrated under vacuum. The residue waspurified with HPLC to give the tittle compound as a light yellow oil 30mg, yield 60%. MS m/e 519.0 (M+H)⁺.

Example 62-{2-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]

ethyl}-6-benzofuran Acetic Acid Hydrochloride Fa) (3-hydroxy-4-iodo-phenyl)-acetic Acid Methyl Ester

To a stirring solution of (3-hydroxy-phenyl)-acetic acid (5.0 g, 0.033mole) in aqueous NH₂OH (100 mL NH₂OH (aqueous) and 50 mL H₂O) at 0° C.was added solid KI (7.6 g, 0.36 mole) and solid 12 (6.0 g, 0.030 mole).The reaction mixture was stirred for 2 h, and then poured into H₂O. Theaqueous mixture was extracted three times with Et₂O, and the organicextracts were combined. The ether extracts were dried over Na₂SO₄,filtered, and concentrated. The crude product was dissolved in MeOH (100mL), conc. HCl (2 mL) was added, and the mixture was heated at refluxovernight. The reaction was cooled to RT and concentrated. The crudemethyl ester was dissolved in EtOAc, and washed two times with H₂O (50mL). The EtOAc layer was dried over Na₂SO₄, filtered, and concentrated.The crude product was purified by preparative HPLC (TMC CombiPrep PDS,75×30 mm, 25 mL/min, acetonitrile: H₂O, UV detection at 254 nm) to give2.67 g (29% yield) of title compound as a white solid. MS(ESI) 292.8(M⁺).

b) 2-(2-hydroxy-ethyl)-6-benzofuran Acetic Acid Methyl Ester

To a stirring solution of (3-hydroxy-4-iodo-phenyl)-acetic acid methylester (1.04 g, 0.0035 mole) and 3-butyn-1-ol (0.5 g, 0.007 mole) in a3:1 solution of toluene/Et₃N (25 mL) was added PPh₃ (70 mg, 0.26 mmol),CuI (68 mg, 0.35 mmol), and Pd(PPh₃)₂Cl₂ (50 mg, 0.07 mmol). The mixturewas heated at 118° C. for 1 h and then cooled to RT. To the reactionmixture was added florisil (2 g) and the mixture was filtered through afritted funnel. The crude benzofuran was concentrated and subjected tocolumn chromatography over silica gel (silica gel 60, EM Science) using40% EtOAc:hexane as eluent to afford 0.59 g (71% yield) of the titlecompound as an oil. MS (ESI) 235.0 (M+H⁺).

c) 2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran Acetic AcidMethyl Ester

To a stirring solution 2-[2-(2-hydroxy-ethyl)-benzofuran]acetic acidmethyl ester (0.33 g, 0.0014 mole) in CH₂Cl₂ (15 mL) at 0° C. was addedEt₃N (0.21 mL, 0.0015 mole) and methanesulfonyl chloride (0.12 mL,0.0015 mole). The reaction mixture was stirred for 3 h at 0° C. Themixture was then poured into cold H₂O, and extracted two times withCH₂Cl₂ (30 mL). The CH₂Cl₂ extracts were washed with saturated aqueousNaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudemesylate (prepared above) was dissolved in CH₃CN (25 mL), and thefollowing reagents were added to the solution: solid K₂CO₃ (194 mg, 1.41mmol) and N-2,2-diphenylethylamine (0.55 g, 0.0014 mole). The reactionmixture was heated overnight at 88° C. The mixture was filtered througha fritted funnel and concentrated. The crude product was purified bypreparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H₂O, UV detection at 254 nm) to give 125 mg (15% yield) of the titlecompound as a viscous oil. MS(ESI) 400.0 (M+H⁺).

d)2-{2-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]ethyl}-6-benzofuranAcetic Acid Methyl Ester

To a stirring solution of2-{2-[(2,2-diphenylethyl)amino]-ethyl}-6-benzofuran acetic acid methylester (160 mg, 0.39 mmol) and 2-chloro-3-trifluoromethylbenzaldehyde (81mg, 0.39 mmol) in CH₂Cl₂ (4 mL) was added sodium triacetoxyborohydride(91 mg, 0.43 mmol) and two drops of glacial acetic acid. The mixture wasstirred for 4 h, and was diluted with EtOAc (10 mL). The mixture waswashed with saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, andsaturated aqueous NaCl. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by columnchromatography over silica (Silica gel 60, EM Science) using 10%EtOAc:Hexane as eluent to afford 0.15 g (64%) of the title compound asan oil. MS(ESI) 606.2 (M⁺).

e)2-{2-[[2-Chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranAcetic Acid Hydrochloride

To a stirring solution of2-{2-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-ethyl}-6-benzofuranacetic acid methyl ester (150 mg, 0.25 mmol) in a 4:1H₂O/THF (3 mL)solution at 0° C. was added LiOH—H₂O (23 mg, 0.55 mmol). The reactionmixture was warmed to RT and stirred overnight. The reaction mixture wasconcentrated to remove the THF and was diluted with H₂O (5 mL). Theaqueous solution was acidified with 1 N HCl (10 mL) and extracted threetimes with EtOAc. The EtOAc extracts were dried over Na₂SO₄, filtered,and concentrated. The resulting tertiary amine was dissolved in Et₂O andacidified with 1 N HCl in Et₂O. The solution was stirred for 20 min. andthen concentrated to afford 122 mg (78% yield) of the title compound asa white solid. MS(ESI) 592.0. (M⁺).

Example 7 LXR Alpha mRNA Levels are Elevated Following Transient MiddleCerebral Artery Occulsion (tMCAO) in the Rat

tMCAO: Transient (90 min) focal cerebral ischaemia was induced in maleSprague Dawley rats, each weighing between 300-350 g. The animals wereinitially anaesthetised with a mixture of 5% halothane, 60% nitrousoxide and 30% oxygen, placed on a facemask and anaesthesia subsequentlymaintained at 1.5% halothane. Middle cerebral artery occlusion (MCAO)was carried out using the intraluminal thread technique as describedpreviously (Zea Longa, et. al., 1989). Parallel groups (n=3 per group)of animals were received either MCA occlusion or sham surgery, in whichan identical procedure was followed but without insertion of thefilament Animals were maintained normothermic throughout the surgicalprocedure, allowed to recover for 1 h in an incubator, before beingsingly housed. Only those animals with a neurological score of 3 1 hpost-occlusion were included in the study (as assessed using a 5-pointscoring system: 0, no deficit; 1, contralateral reflex; 2, weakenedgrip; 3, circling; 4, immobile; 5, dead). Animals were maintained for upto 4 weeks.

SYBRman quantitative PCR: The left (lesioned) cerebral cortex wasdissected from each rat. All tissues were snap frozen in liquid nitrogenimmediately after dissection and stored at −80° C. Tissue samples fromeach group were homogenised in TRIzol reagent (Life Technologies Inc.,Gaithersburg, Md., USA) using 1 ml of TRIzol per 50 mg of tissue. TotalRNA was extracted from the tissue according to the manufacturer'ssuggested protocol with the addition of an extra chloroform extractionstep and phase separation, and an extra wash of the isolated RNA in 70%ethanol. The RNA was resuspended in PCR grade water and theconcentration calculated by A₂₆₀ measurement. RNA quality was assessedby electrophoresis on a 1% agarose gel. Equal quantities of RNA fromeach animal in a group were pooled. First strand cDNA was synthesisedfrom 1 μg of each RNA sample; 0.01M DTT, 0.5 mM each dNTP, 0.5 μgoligo(dT) primer, 40 U RNAseOUT ribonuclease inhibitor (LifeTechnologies Inc.), 200 U SuperscriptII reverse transcriptase (LifeTechnologies Inc.). Triplicate reverse transcription reactions wereperformed along with an additional reaction in which the reversetranscriptase enzyme was omitted to allow for assessment of genomic DNAcontamination in each sample. The resulting cDNA products were dividedinto twenty aliquots using a Hydra 96 robot (Robbins Scientific,Sunnyvale, Calif., USA) for parallel SYBRman PCR reactions usingdifferent primer sets for quantification of multiple cDNA sequences.SYBRman PCR was carried out using an ABI prism 7700 sequence detector(Applied Biosystems, Foster City, Calif., USA) on the cDNA samples;using SYBRgreen PCR Master Mix (Applied Biosystems) 50° C. for 2minutes, 95° C. for 10 minutes followed by forty cycles of 95° C. for 15seconds, 60° C. for 1 minute. Additional reactions were performed oneach 96 well plate using known dilutions of rat genomic DNA (ClontechLaboratories Inc., Palo Alto, Calif., USA) as a PCR template to allowconstruction of a standard curve relating threshold cycle to initialtemplate copy number.

Primer sequences were as follows: LXR-alpha left primer:AGTGTTTGCACTTCGCCTGC LXR-alpha right primer: GTAAGCTTCAGCTGCGTGGC

Example 8 LXR Agonists Promote Neurite Outgrowth

Hippocampal neurons: The hippocampi of gestational day 18 rat embryoswere dissected out, incubated in trypsin (0.08%, 30 min at 37° C.) anddissociated mechanically (16). Hippocampal cells were resuspended inneurobasal medium supplemented with B27, anti-oxidants, 1 mM glutamine,25 μM glutamate, 1 mM pyruvate. For outgrowth assays, cells were platedat a density of 3000 cells/well into 96 well dishes that had previouslybeen coated with poly-D-lysine followed by 10% FCS and cultured for 48hours.

Cortical neurons: Cortex from gestational day 18-20 rat embryos werecollected in HBSS on ice. Cells were dissociated as described forhippocampal neurons. Cells were pelted (200 g, 5 mins and resuspended inmedium as described for hippocampal cells. Cells were plated at 6000cells/well and cultured for 24 hours.

The test compound was solubilised in DMSO and added to culture medium attime of cell plating at a dilution of 1:1000. Vehicle only (1:1000) wasadded to culture medium of untreated controls. Cells were fixed with 4%paraformaldehyde for 1 hour on ice, washed with PBS and stained usingCoomassie. Assays were quantified using a KS300 image analysis system(Imaging Associates, UK). For each cell measured, the length from theedge of the cell to the end of the longest neurite was measured for 100cells/well for each treatment in triplicate. All data are means and SEMpooled from three independent experiments. Results are expressed as apercentage of the length of neurites of cells treated with vehiclealone. Concentration of test HC neurons CR neurons compound (μm) Example1 22(R) hydroxychol. Example 1 0 100 (6.2)   100 (5.4)   100 (1) 0.3 109(6.25) 115.9 (6.02)   105 (1.79) 1.0 113 (5.05)   116 (7.45)   110 (2.4)3.0 120 (7.75) 129.9 (4.12)  123.6 (6.6) 10.0 147 (11.8) 127.9 (6.18)126.23 (2.5)

Figures in parentheses represent the standard error from pooled datafrom three independent experiments (HC) or from triplicate wells in asingle experiment (CR).

Example 9 LXR Agonists are Anti-Neuroinflammatory

NTW8 mouse microglial cells were plated into a 96 well plate at adensity of 2×10⁵ cells/well in DMEM supplemented with 10% FCS, 2 mMglutamine, 10 ng/ml basic fibroblast growth factor (R&D Systems) and N-2(Gibco). Next day, cell were stimulated for 24 hrs in DMEM containing 10ng/ml LPS (Sigma) and 20 U/ml IFN-γ (Gibco) in the presence ofincreasing concentrations of the test compound solubilised in DMSO.Media was removed after 24 hrs and analysed by ELISA for secreted IL-6,TNF-α (R&D systems) and PGE2 (Amersham) or via a Greiss assay for nitricoxide (NO) production. Cell viability was assessed by an MTT assay(Promega). All data are means and SEM pooled from two independentexperiments. Results are expressed as a percentage of the LPS\INF-γstimulated control cells treated with DMSO alone.

FIG. 2 shows that Example 1 inhibited the secretion of pro-inflammatorymediators (IL-6, PGE2, TNF-α and NO) from LPS INF-γ stimulated microgliacells.

Example 10 LXR Agonists Promote Astroglial Cell Cholesterol Efflux

It has recently been reported that astroglial cells increase synapseplasticity by secreting cholesterol-rich lipoprotein particles (22).These particles are internalized by neurons, leading to an increase inthe number and efficacy of synapses. Therefore it is possible thatcompounds which stimulate astroglial cell cholesterol efflux wouldpromote synaptogenesis, and thus aid nerve regeneration.

Primary murine neuronal cultures were prepared from C57 B1/6 miceessentially as described elsewhere (23). In brief, embryonic day 18fetuses were collected by caesarian section, their brains removed andthe cerebral cortices dissected from the rest of the brain. The tissuewas rinsed during these steps several times in Ca²⁺- and Mg²⁺-freeHank's balanced salt solution (HBSS, containing 1 mM HEPES, GIBCO).After the meninges were removed with forceps, the tissue was minced andincubated for 15 minutes at 37° C. in 0.25% trypsin (Sigma) in HBSS. Thetissue was then washed twice in HBSS and twice in neuronal plating media(minimal essential media [MEM] containing 3 mg/ml glucose, 5% fetalbovine serum [FBS; GibcoBRL], 5% horse serum [HS; GibcoBRL], 100 U/mlpenicillin/100 μg/ml streptomycin [Irvine Scientific] and 2 mM glutamine[Irvine Scientific]) to which 10 μg/ml DNAseI (Sigma) had been added.The tissue was then triturated and spun at 3000×g for 10 minutes. Theresulting cell pellet was resuspended in plating media, and trypanblue-excluding surviving cells were counted in a hemacytometer. Cellswere plated into 6-well plates at 1.35×10⁶ cells per well and maintainedat 37° C. in 5% CO₂/95% air in a humidified incubator. The next morning,the plating media from some cultures was carefully withdrawn andreplaced with serum-free media (Neurobasal media containing B27supplement [both from GibcoBRL], 100 U/ml penicillin/100 μg/mlstreptomycin, and 0.5 mM glutamine). These cells were fed by half-volumeexchange with fresh serum-free media on day 3 in culture. Serum-freegrowth conditions restrict glial outgrowth such that the resultingcultures are >95% neuronal. The remaining cells were maintained in thesame serum-containing plating media without media exchange to establishcultures composed of neurons and glia in an approximate ratio of 60:40(23). Cells were used in cholesterol efflux assays starting on cultureday 6.

Murine astroglia were obtained from postnatal day 1 pups. Briefly, pupswere decapitated, their brains removed, and the cerebral corticesprepared as described previously (45), except that astrocyte platingmedia was used (Dulbecco's modified eagle media [DMEM] containing 4mg/ml glucose, 5% FBS and 5% HS [GibcoBRL or Irvine Scientific], 100U/ml penecillin/100 μg/ml streptomycin, 25 mM HEPES, and 2-4 mMglutamine). Glia were grown in T75 flasks at a density of approximately2 brains per flask. Cells were fed once weekly by complete mediaexchange in maintenance media (DMEM containing 4.5 mg/ml glucose, 10%FBS, 100 U/ml penecillin/100 μg/ml streptomycin, 25 mM HEPES, and 6 mMglutamine). By visual inspection, these cultures were nearly entirelyastroglial with <1% contamination with microglia. After 7-14 days invitro, cells were collected by trypsinization, counted in ahemacytometer, and plated into 6-well plates at 50-100,000 cells perwell in maintenance media. Cholesterol efflux assays were begun after 3days' growth, by which time the cells were approximately 40% confluent.

Cholesterol efflux assays were performed as described elsewhere (24)with some modifications. For astrocytes, the culture media was removedand replaced with 1 ml/well DMEM containing 4.5 mg/ml glucose, 5% FBS,100 U/ml penecillin/100 μg/ml streptomycin, 25 mM HEPES, and 6 mMglutamine supplemented with 0.5% BSA and 5 W [1,2-³H(N)]-cholesterol (1mCi/ml ethanolic stock). Twenty-four hours later, cells were washed oncein serum-free DMEM containing glucose, penicillin/streptomycin, HEPES,and glutamine and then incubated for 24 hours in the same mediasupplemented with 0.5% BSA and various drugs or DMSO vehicle. The nextday, cells were washed twice in serum-free media and then incubated fora further 24 hours in 1 ml/well of serum-free media supplemented withdrugs or DMSO. Human ApoA-1 was added to some cultures to serve as anexogenous cholesterol acceptor molecule. At the end of this incubation,culture media was collected and spun in a microfuge. Adherent cells werewashed three times in PBS and extracted for 1 hr in 1 ml per wellhexane:isopropanol (3:2 vol:vol). Two hundred microliters of the culturemedia supernatant and 200 μl of the cell extract were counted fortritium in 2 ml Packard Ultima Gold Scint. Cholesterol efflux fromneurons was examined in much the same way except that cells were alwayswashed and incubated with the neuronal serum-free culturing mediadescribed above. On the first day of the efflux experiment, neuronsreceived a half-volume media change with media containing 10 μl[1,2-³H(N)]-cholesterol. Efflux is expressed as percent of the totalradiolabeled cholesterol pool present in the cultures. Cholesterolefflux as a percentage of total [³H] cholesterol Compound AstrocytesNeurons Vehicle 1.835 (0.826) 1.256 (0.329) Example 1  4.722 (0.783)*1.252 (0.179) T0901317  4.370 (0.561)* 1.427 (0.031)

Basal efflux from astrocyte cultures was enhanced by each LXR agonists.Data reflect 3 independent determinations and are representative of 4separate experiments. Figures in parentheses represent the standarddeviation. *, p<0.05 by t-test relative. LXR agonists promotecholesterol efflux from primary astroglial cells, but not neurons.

Example 11 LXR Agonists Upregulate Target Gene Expression in MurinePrimary Astrocyte and Neuron Cell Cultures

Total RNA was isolated from tissue and cell culture samples using TRIzolreagent (GibcoBRL). Briefly, tissue samples were thawed directly in 1 mlTrizol/50 mg tissue and homogenized with a polytron. To facilitaterecovery of nucleic acid, 100 μg glycogen (Ambion) was added. Culturedcells were lysed in 1 ml Trizol containing 100 μg glycogen per well.Samples were then extracted in chloroform and spun at 4° C. at 11,000×gfor 15 min. The aqueous phase was collected and the RNA was precipitatedwith the addition of isopropanol. The samples were then spun at 11,000×gat 4° C. for 15 min, the pellet washed in 75% ethanol, dried, anddissolved in water. Samples were stored at −70° C. until use.

Total RNA samples were diluted to 100 μg/ml and treated with 40 units/mlRNA-free DNAse-I (Ambion) for 30 min at 37° C. followed by inactivationat 75° C. for 5 min. Samples were quantitated by spectrophotometry orwith the RiboGreen assay (Molecular Probes) and diluted to aconcentration of 10 ng/μl. Samples were then assayed in duplicate ortriplicate 25-μl reactions using 25 ng RNA per reaction with PerkinElmer chemistry on an ABI Prism 7700 (Perkin Elmer) according tomanufacturer's instructions. Gene-specific primers were used at 7.5 or22.5 pmol per reaction, optimized for each gene examined, and thegene-specific probe was used at 5 pmol per reaction. Primers and probewere synthesized by Keystone Labs (Camarillo, Calif.). In this system,the probe is degraded by Taq polymerase during the amplification phase,releasing the fluorescent tag from its quenched state; amplificationdata is expressed as the number of PCR cycles required to elevate thefluorescence signal beyond a threshold intensity level. Fold inductionvalues were calculated by subtracting the mean threshold cycle number(Ct) for each treatment group from the mean Ct for the vehicle group andraising 2 to the power of this difference.

Total RNA prepared from sister cultures treated in parallel was used toprofile the expression of ABCA1, ABCG1, and SREBP1c. Expression levelsfor each gene in neurons and astrocytes were normalized to thevehicle-treated group and are from 2-3 separate experiments. Target geneexpression was more highly induced by drug treatment in astrocytecultures than neuronal cultures. Compound ABCA1 Astro- ABCG1 SREBP-1ccytes Neurons Astrocytes Neurons Astrocytes Neurons Vehicle 1.0 1.0 1.01.0 1.0 1.0 Example 1 11.8 2.8 14.9 2.8 13.9 3.1 T0901317 18.4 3.0 12.53.1 20.2 3.1

Example 12 LXR Agonists Upregulate Target Gene Expression in the CNS

Adult male C57 B1/6 mice (3 per group) were dosed by oral gavage withthe LXR agonists Example 1, T0901317, or vehicle (0.5% methylcellulose).Example 1 was delivered at 10 mg kg twice daily, while T0901317 wasadministered at 50 mg/kg once daily. After 3 or 7 days' treatment,animals were killed and their brains removed. The cerebellum and bothhippocampi were dissected and snap frozen in liquid nitrogen for RNAisolation. Total RNA was prepared from the hippocampus and cerebellum(black bars) and analyzed for gene expression patterns using QRT-PCR (asdescribed above). Expression levels for each gene in each tissue werenormalized to the average expression level in the vehicle group. BothLXR agonists enhanced ABCA1 expression relative to the vehicle-treatedgroup, with the effect most pronounced in the cerebellum after 3 days'treatment. Compound ABCA1 ABCG1 SREBP-1c HC CB HC CB HC CB Vehicle  1.0(0.092)  1.0 (0.049)  1.0 (0.112)  1.0 (0.153)  1.0 (0.060)  1.0 (0.076)Example 1 1.57 (0.348) 2.13 (0.354) 1.14 (0.212) 1.52 (0.073) 2.22(0.600) 2.05 (0.427) T0901317 2.70 (0.304) 3.66 (0.389) 1.22 (0.098)2.31 (0.081) 2.68 (0.209) 3.44 (0.632)

Compound ABCA1 ABCG1 SREBP-1c HC CB HC CB HC CB Vehicle  1.0 (0.122) 1.0 (0.044)  1.0 (0.072)  1.0 (0.060)  1.0 (0.096)  1.0 (0.174) Example1 1.26 (0.162) 1.43 (0.302) 0.89 (0.045) 1.17 (0.142) 0.71 (0.327) 1.75(0.236) T0901317 2.69 (0.175) 2.94 (0.084) 1.37 (0.092) 1.80 (0.116)2.16 (0.110) 2.97 (0.557)

REFERENCES

-   1. Fawcett & Asher, 1999. The glial scar and central nervous system    repair. Brain Res. Bulletin, 49 : 377-391-   2. Horner & Gage. Regenerationg the damaged central nervous system.    2000, Nature 407 963-970-   3. McGeer P L, McGeer E G. (1995) The inflammatory response system    of brain: implications for therapy of Alzheimer and other    neurodegenerative diseases. Brain Res Brain Res Rev. 21(2):195-218-   4. Peet D J, Janowski B A, Mangelsdorf D J. The LXRs: a new class of    oxysterol receptors. Curr Opin Genet Dev 1998;8(5):571-5.-   5. Apfel R, Benbrook D, Lernhardt E, Ortiz M A, Salbert G, Pfahl M.    A novel orphan receptor specific for a subset of thyroid    hormone-responsive elements and its interaction with the    retinoid/thyroid hormone receptor subfamily. Mol Cell Biol 1994;    14(10):7025-35.-   6. Teboul M, Enmark E, Li Q, Wikstrom A C, Pelto-Huikko M,    Gustafsson J A. OR-1, a member of the nuclear receptor superfamily    that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad    Sci USA 1995;92(6):2096-100.-   7. Song C, Kokontis J M, Hiipakka R A, Liao S. Ubiquitous receptor:    a receptor that modulates gene activation by retinoic acid and    thyroid hormone receptors. Proc Natl Acad Sci USA    1994;91(23):10809-13.-   8. Willy P J, Umesono K, Ong E S, Evans R M, Heyman R A, Mangelsdorf    D J. LXR, a nuclear receptor that defines a distinct retinoid    response pathway. Genes Dev 1995; 9(9):1033-45.-   9. Peet D J, Turley S D, Ma W, Janowski B A, Lobaccaro J M, Hammer R    E, et al. Cholesterol and bile acid metabolism are impaired in mice    lacking the nuclear oxysterol receptor LXR alpha. Cell 1998;    93(5):693-704.-   10. Luo Y, Tall A R. Sterol upregulation of human CETP expression in    vitro and in transgenic mice by an LXR element. J Clin Invest 2000;    105(4):513-20.22-   11. Repa J J, Liang G, Ou J, Bashmakov Y, Lobaccaro J M, Shimomura    I, et al. Regulation of mouse sterol regulatory element-binding    protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and    LXRbeta. Genes Dev 2000; 14(22):2819-30.-   12. Schultz J R, Tu H, Luk A, Repa J J, Medina J C, Li L, et al.    Role of LXRs in control of lipogenesis. Genes Dev    2000;14(22):2831-8.-   13. Laffitte B A, Repa J J, Joseph S B, Wilpitz D C, Kast H R,    Mangelsdorf D J, et al. LXRs control lipid-inducible expression of    the apolipoprotein E gene in macrophages and adipocytes. Proc Natl    Acad Sci USA 2001; 98(2):507-12.-   14. Costet P, Luo Y, Wang N, Tall A R. Sterol-dependent    transactivation of the ABC1 promoter by the liver X    receptor/retinoid X receptor. J Biol Chem 2000; 275(36):28240-5.-   15. Repa J J, Turley S D, Lobaccaro J A, Medina J, Li L, Lustig K,    et al. Regulation of absorption and ABC1-mediated efflux of    cholesterol by RXR heterodimers. Science 2000; 289(5484): 1524-9.-   16. Venkateswaran A, Repa J J, Lobaccaro J M, Bronson A, Mangelsdorf    D J, Edwards P A. Human white/murine ABC8 mRNA levels are highly    induced in lipid-loaded macrophages. A transcriptional role for    specific oxysterols. J Biol Chem 2000; 275(19): 14700-7.-   17. Venkateswaran A, Laffitte B A, Joseph S B, Mak P A, Wilpitz D C,    Edwards P A, et al. Control of cellular cholesterol efflux by the    nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA 2000;    97(22):12097-102.-   18. Schwartz K, Lawn R M, Wade D P. ABC1 gene expression and    ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem    Biophys Res Commun 2000;274(3): 794-802.-   19. Schmidt, A., Vogel, R., Holloway, M. K., Rutledge, S. J.,    Friedman, O., Yang, Z., Rodan, G. A. and Friedman, E. Transcription    control and neuronal differentiation by agents that activate the LXR    nuclear receptor family. (1999) Mol. and Cell. Endoc., 155: 51-60.-   20. Virley, D., Beech, J. S., Smart, S. C., Williams, S. C. Hodges,    H & Hunter, A. J. A temporal MRI assessment of neuropathology after    transient middle cerebral artery occlusion in the rat; correlations    with behaviour. J. Cereb. Blood Flow Metab. 2000, 20, 563-582-   21. Skaper S D, Facci L, Milani D, Leon A, and Toffano G (1990). In    Methods in Neurosciences, Vol 2, Academic Press, San Diego.-   22. Mauch D H, Nagler K, Schumacher S, Goritz C, Muller E C, Otto A,    Pfrieger F W. (2001) CNS synaptogenesis promoted by glia-derived    cholesterol. Science. 294(5545): 1354-7-   23. Whitney, K. D. & McNamara, J. O. Glu R3 autoantibodies destroyy    neural cells in a complement dependent manner modulated by    complement regulatory proteins. Journal of Neuroscience. 2000;    20(19):7307-16-   24. Oliver, W. J., Shenk, J. L., Snaith, M. R., Russell, C. S.,    Plunket, K. D., Bodkin, N. L., Lewis, M. C., Winegar, D. A.,    Sznaidman, M. L., Lambert, M. H., Xu H. E., Sternbach, D. D.,    Kliewer, S. A., Hansen, B. C., and Willson, T. M. A selective    peroxisome proliferator-activated receptor agonist promotes reverse    cholesterol transport (2001) Proc Natl Acad Sci USA 98(9),    5306-5311.-   25. Repa J J, Mangelsdrof D J 2000 The role of orphan nuclear    receptors in the regulation of cholesterol homeostasis. Annu Rev    Cell Dev Biol 16:459-481.-   26. Teboul M, Enmark E, Li Q, Wikstrom A C, Pelto-Huikko M,    Gustafsson J A 1995 OR-1, a member of the nuclear receptor    superfamily that interacts with the 9-cis-retinoic acid receptor.    Proc Natl Acad Sci USA 92:2096-2100.-   27. Janowski B A, Willy P J, Devi T R, Falck J R, Mangelsdorf D J    1996 An oxysterol signalling pathway mediated by the nuclear    receptor LSR alpha. Nature 383:728-731.-   28. Lehman J M, Kliewer S A, Moore L B et al. 1997 Activation of the    nuclear receptor LXR by oxysterols defines a new hormone response    pathway. J. Biol. Chem. 272:3137-3140.-   29. Dietschy J M, Turley S D 2001 Cholesterol metabolism in the    brain. Curr Opin Lipidol 12:105-112.-   30. Lutjohann, D, Breuer O, Ahlborg G et al. 1996 Cholesterol    homeostasis in human brain: evidence for an age-dependent flux of    24S-hydroxycholesterol from the brain into the circulation. Proc    Natl Acad Sci USA 93: 9799-9804.-   31. Bjorkhem I, Lutjohann D, Breuer O, Sakinis A, Wennmalm A 1997    Importance of a novel oxidative mechanism for elimination of brain    cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in    rat brain as measured with 1802 techniques in vivo and in vitro. J    Biol Chem 272: 30178-30184.-   32. Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G,    Wahren J 1998 Cholesterol homeostasis in human brain: turnover of    24S-hydroxycholesterol and evidence for a cerebral origin of most of    the oxysterol in the circulation. J. Lipid Res. 39: 1594-1600.-   33. Xie C, Burns D K, Turley S D, Dietschy J M 2000 Cholesterol is    sequestered in the brains of mice with Niemann-Pick type C disease    but turnover is increased. J Neuropathol Exp Neurol 59: 1106-1117.-   34. Lutjohann D, Papassotiropoulos A, Bjorkhem I et al. 2000 Plasma    24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and    vascular demented patients. J Lipid Res 41: 195-198.-   35. Notkola I L, Sulkava R, Pekkanen J et al 1998 Serum total    cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's    disease. Neuroepidemiology 17: 14-20.-   36. Kuo Y M, Emmerling M R, Bisgaier C L et al. 1998 Elevated    low-density lipoprotein in Alzheimer's disease correlates with brain    abeta 1-42 levels. Biochem Biosphys Res Commun 252: 711-715.-   37. Wolozin B, Kellman W, Ruosseau P, Celesia G G, Siegel G 2000    Decreased prevalence of Alzheimer disease associated with    3-hydroxy-3-methyglutarly coenzyme A reductase inhibitors. Arch    Neurol 57: 1439-1443.-   38. Jick H, Zornberg G L, Jick S S, Seshardi S, Dracbman D A 2000    Statins and the risk of dementia. Lancet 356:1627-1637.-   39. Strittmatter W J, Saunders A M, Schmechel D et al. 1993    Apolipoprotein E: high-avidity binding to beta-amyloid and increased    frequency of type 4 allele in late-onset familial Alzheimer disease.    Proc Natl Acad Sci USA 90: 1977-1981.-   40. Roses A D, Saunders A M, Alberts M A et al. 1995 Apolipoprotein    E E4 allele and risk of dementia. JAMA 273:374-375; discussion    375-376.-   41. Strittmatter W J, Roses A D 1996 Apolipoprotein E and    Alzheimer's disease. Annu Rev Neurosci 19:53-77.-   42. Jarvik G P, Wijsman E M, Kukull W A, Schellenberg G D, Yu C,    Larson E B 1995 Interactions of apolipoprotein E genotype, total    cholesterol level, age, and sex in prediction of Alzheimer's    disease: a case-control study. Neurology 45:1092-1096.-   43. Liu H C, Hong C J, Wang S J et al. 1999 ApoE genotype in    relation to AD and cholesterol: a study of 2,326 Chinese adults.    Neurology 53:662-966.-   44. Lund E G, Guileyardo J M, Russell D W 1999 cDNA cloning of    cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in    the brain. Proc Natl Acad Sci USA 96:7238-7243.

The above description fully discloses how to make and use the presentinvention. However, this invention is not limited to the particularembodiments described hereinabove, but includes all modification thereofwithin the scope of the appended claims and their equivalents. Thoseskilled in the art will recognize through routine experimentation thatvarious changes and modifications can be made without departing from thescope of this invention. The various references to journals, patents andother patent applications that are cited herein are incorporated byreference herein as though fully set forth.

1. A method for treating a patient suffering from a disease selectedfrom the group consisting of: stroke, Alzheimer's disease,fronto-temporal dementias, peripheral neuropathy, Parkinson's disease,dementia with Lewy bodies, Huntington's disease, amyotrophic lateralsclerosis, and multiple sclerosis, said method comprising the step ofadministering to said patient an effective amount of an LXR modulator incombination with a carrier.
 2. The method as claimed in claim 1, whereinsaid LXR modulator is selected from the group consisting of: an LXRagonist and an LXR antagonist.
 3. A method for promoting cholesterolefflux in at least one astroglial cell, said method comprising the stepof: contacting said at least one astroglial cell with acholesterol-efflux-promoting effective amount of an LXR modulator incombination with a carrier.
 4. The method according to claim 3, whereinsaid LXR modulator is selected from the group consisting of: an LXRagonist and an LXR antagonist.
 5. A method for treating a patientsuffering from a disease or disorder characterised by neurondegeneration, inflammation in the CNS, injury or impaired plasticity,said method comprising the step of administering to said patient aneffective amount of an LXR modulator in combination with a carrier. 6.The method according to claim 5, wherein said LXR modulator is selectedfrom the group consisting of: an LXR agonist and an LXR antagonist. 7.The method according to claim 1 or, wherein the disease is selected frompsychiatric disorders such as schizophrenia and depression.
 8. Themethod according to claim 1, wherein the disease is selected fromconditions associated with head or spinal cord injury, including trauma.9. The method according to claim 1, wherein the LXR modulator comprisesa compound of formula (I)

wherein: Ar represents an aryl group; R¹ is —OH, —O—(C₁-C₇)alkyl,—OC(O)—(C₁-C₇)alkyl, —O—(C₁-C₇)heteroalkyl, —OC(O)— (C₁-C₇)heteroalkyl,—CO₂H, —NH₂, —NH(C₁-C₇)alkyl, —N((C₁-C₇)alkyl)₂ or—NH—S(O)₂—(C₁-C₅)alkyl; R² is (C₁-C₇)alkyl, (C₁-C₇)heteroalkyl, aryl andaryl(C₁-C₇)alkyl; X¹, X², X³, X⁴, X⁵ and X⁶ are each independently H,(C₁-C₅)alkyl, (C₁-C₅)hetroalkyl, F or Cl, with the proviso that no morethan three of X¹ through X⁶ are H, (C₁-C₅)alkyl or (C₁-C₅)heteroalkyl;and Y is —N(R¹²)S(O)_(m)—, —N(R¹²)S(O)_(m)N(R¹³), —N(R¹²)C(O)—,—N(R¹²)C(O)N(R¹³), —N(R¹²)C(S)— or —N(R¹²)C(O)O—, wherein R¹² and R¹³are each independently hydrogen, (C₁-C₇)aryl, (C₁-C₇)heteroalkyl, aryland aryl(C₁-C₇)alkyl, and optionally when Y is —N(R¹²)S(O)_(m)— or—N(R¹²)S(O)_(m)N(R¹³)—, R¹² forms a five, six or seven-membered ringfused to Ar or to R² through covalent attachment to Ar or R²,respectively. In the above Y groups, the subscript m is an integer offrom 1 to 2; or a pharmaceutically acceptable derivative thereof
 10. Themethod according to claim 1, wherein the LXR modulator comprises acompound of formula (II):

wherein: X is OH or NH₂; p is 0-6; each R¹ and R² are the same ordifferent and are each independently selected from the group consistingof H, C₁₋₈alkyl, C₁₋₈alkoxy and C₁₋₈thioalkyl; Z is CH or N; when Z isCH, k is 0-4; when Z is N, k is 0-3; each R³ is the same or differentand is independently selected from the group consisting of halo, —OH,C₁₋₈alkyl, C₂₋₈alkenyl, C₁₋₈alkoxy, C₂₋₈alkenyloxy, —S(O)_(a)R⁶, —NR⁷R⁸,—COR⁶, COOR⁶, R¹⁰COOR⁶, OR¹⁰COOR⁶, CONR⁷R⁸, —OC(O)R⁹, —R¹⁰NR⁷R⁸,—OR¹⁰NR⁷R⁸, 5-6 membered heterocycle, nitro, and cyano; a is 0, 1 or 2;R⁶ is selected from the group consisting of H, C₁₋₈alkyl, C₁₋₈alkoxy andC₂₋₈alkenyl; each R⁷ and R⁸ are the same or different and are eachindependently selected from the group consisting of H, C₁₋₈alkyl,C₂₋₈alkenyl, C₃₋₈alkynyl; R⁹ is selected from the group consisting of H,C₁₋₈alkyl and —NR⁷R⁸; R¹⁰ is C₁₋₈alkyl; n is 2-8; q is 0 or 1; R⁴ isselected from the group consisting of H, C₁₋₈alkyl, C₁₋₈alkenyl, andalkenyloxy; Ring A is selected from the group consisting ofC₃₋₈cycloalkyl, aryl, 4-8 membered heterocycle, and 5-6 memberedheteroaryl; each ring B is the same or different and is independentlyselected from the group consisting of C₃₋₈cycloalkyl and aryl: or apharmaceutically acceptable derivative thereof.
 11. The method accordingto claim 1, wherein the LXR modulator comprises a compound of formula(III):

wherein: X is selected from C₁-C₈ alkyl, halo, —OR¹⁰, —NR¹⁴R¹⁵, nitro,cyano, —COOR¹⁰, —COR¹³, —OCOR¹³, —CONR¹⁴R¹⁵, —N(R¹⁷)COR¹³,—N(R¹⁷)CONR¹⁴R¹⁵, —N(R¹⁷)COOR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵,—N(R¹⁷)SO₂R¹⁶, and a 5 or 6-membered heterocyclic group; or X and anadjacent R³, taken together with the atoms to which they are bonded,form an alkylenedioxy moiety; Z is CH, CR³ or N, wherein when Z is CH orCR³, k is 0-4 and t is 0 or 1, and when Z is N, k is 0-3 and t is 0; Yis selected from —O—, —S—, —N(R¹⁰)—, and —C(R⁴)(R⁵)—; W¹ is selectedfrom C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl and Het, wherein said C₁-C₈alkyl, C₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted orsubstituted with one or more groups independently selected from halo,cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰,—C₀-C₆ alkyl-SO₃H, —C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆alkyl-SOR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆alkyl-OC(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆ alkyl-NR¹¹COR¹³, where said C₁-C₆alkyl, is optionally unsubstituted or substituted by one or more halosubstituents; W² is selected from H, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹¹, —C₀-C₆alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-OCOR¹³, —C₀-C₆alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹² CONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹COR¹³,—C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl,wherein said C₁-C₆ alkyl is optionally unsubstituted or substituted byone or more halo substituents, and wherein the C₃-C₇ cycloalkyl, Ar andHet moieties of said —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆alkyl-C₃-C₇ cycloalkyl are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W³ is selected from thegroup consisting of: H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R^(o), —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; Q isselected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹²—C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; p is 0-8; n is 2-8; m is 0or 1; q is 0 or 1; t is 0 or 1; each R¹ and R² are independentlyselected from H, halo, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het,—C₁-C₆ alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R² togetherwith the carbon to which they are attached form a 3-5 memberedcarbocyclic or heterocyclic ring, wherein said heterocyclic ringcontains one, or more heteroatoms selected from N, O, and S, where anyof said C₁-C₆ alkyl is optionally unsubstituted or substituted by one ormore halo substituents; each R³ is the same or different and isindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆alkyl-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SR₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₀-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R⁴ and R⁵ isindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁶ and R⁷ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁸ and R⁹ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁰ is selected fromH, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; each R¹¹ and each R¹² areindependently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇cycloalkyl, or R¹¹ and R¹² together with the nitrogen to which they areattached form a 4-7 membered heterocyclic ring which optionally containsone or more additional heteroatoms selected from N, O, and S; R¹³ isselected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁴ andR¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇cycloalkyl, —C₀-C₆ alkyl-S(O), —C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar,—C₀-C₆ alkyl-S(O)_(x)-Het, —C₆-C₆ alkyl-S(O), —C₃-C₇ cycloalkyl, —C₀-C₆alkyl-NH-Het, —C₀-C₆ alkyl-NH—C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-N(C₁-C₄alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆ alkyl-N(C₁-C₄alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R¹⁵, togetherwith the nitrogen to which they are attached, form a 4-7 memberedheterocyclic ring which optionally contains one or more additionalheteroatoms selected from N, O, and S, wherein said C₁-C₆ alkyl isoptionally substituted by one or more of the substituents independentlyselected from the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆alkyl), —N(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl),unsubstituted —OC₁-C₆ alkyl, —CO₂H, —CO₂(unsubstituted C₁-C₆ alkyl),—CONH₂, —CONH (unsubstituted C₁-C₆ alkyl), —CON (unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl), —SO₃H, —SO₂NH₂, —SO₂NH (unsubstitutedC₁-C₆ alkyl) and —SO₂N (unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆alkyl); R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; and R¹⁷is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or —C₀-C₆ alkyl-Het; or apharmaceutically acceptable salt or solvate thereof.
 12. The methodaccording to claim 1, wherein the LXR modulator comprises a compound offormula (IV):

wherein: X is CH or N; Y is N(R¹⁰), O, or S, wherein t is 0 or 1 when Yis N(R¹⁰) or O, and t is 0 when Y is S; U is selected from halo, —OR¹⁰,—NR¹⁴R¹⁵, nitro, cyano, —COOR¹⁰, —COR¹³, —OCOR¹³, —CONR¹⁴R¹⁵,—N(R¹⁴)COR¹³, —SO₃H, —SO₂NR¹⁴R¹⁵, —C(═NR¹⁷)NR¹⁴R¹⁵, —N(R¹⁴)SO₂R¹⁶, and a5 or 6-membered heterocyclic group; A is a phenyl fused ring moiety or apyridyl fused ring moiety, wherein when A is a phenyl ring moiety, k is0-3 and t is 0 or 1 and when A is a pyridyl ring moiety, k is 0-2 and tis 0; W¹ is selected from C₃-C₈ cycloalkyl, aryl and Het, wherein saidC₃-C₈ cycloalkyl, Ar and Het are optionally unsubstituted or substitutedwith one or more groups independently selected from halo, cyano, nitro,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W² is selected from H,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C₀-C₆ alkyl-NR¹¹R¹²,—C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹¹R¹²—C₀-C₆alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents, andwherein the C₃-C₇ cycloalkyl, Ar and Het moieties of said —C₀-C₆alkyl-Het, —C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl areoptionally unsubstituted or substituted with one or more groupsindependently selected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰,—C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —CO—C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹², where said C₁-C₆ alkyl, is optionally unsubstituted orsubstituted by one or more halo substituents; W³ is selected from thegroup consisting of: H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OCONR¹¹R¹², —C₀-C₆ alkyl-NR¹¹CONR¹²R¹²,—C₀-C₆ alkyl-NR¹¹COR¹³, —C₀-C₆ alkyl-Het, —C₁-C₆ alkyl-Ar and —C₁-C₆alkyl-C₃-C₇ cycloalkyl, wherein said C₁-C₆ alkyl is optionallyunsubstituted or substituted by one or more halo substituents; Q isselected from C₃-C₈ cycloalkyl, Ar and Het; wherein said C₃-C₈cycloalkyl, Ar and Het are optionally unsubstituted or substituted withone or more groups independently selected from halo, cyano, nitro, C₁-C₆alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆alkyl-C(O)SR¹⁰, —C₀-C₆ alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H,—C₀-C₆ alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, where said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; p is 0-8; n is 2-8; m is 0or 1; q is 0 or 1; t is 0 or 1; each R¹ and R² are independentlyselected from H, halo, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-NR¹¹R¹², —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SR¹⁰, —C₁-C₆ alkyl-Het,—C₁-C₆ alkyl-Ar and —C₁-C₆ alkyl-C₃-C₇ cycloalkyl, or R¹ and R² togetherwith the carbon to which they are attached form a 3-5 memberedcarbocyclic or heterocyclic ring, wherein said heterocyclic ringcontains one, or more heteroatoms selected from N, O, and S, where saidC₁-C₆ alkyl is optionally unsubstituted or substituted by one or morehalo substituents; each R³ is the same or different and is independentlyselected from halo, cyano, nitro, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-CO₂R¹⁰, —C₀-C₆ alkyl-C(O)SR¹⁰, —C₀-C₆alkyl-CONR¹¹R¹², —C₀-C₆ alkyl-COR¹³, —C₀-C₆ alkyl-NR¹¹R¹², —C₀-C₆alkyl-SR¹⁰, —C₀-C₆ alkyl-OR¹⁰, —C₀-C₆ alkyl-SO₃H, —C₀-C₆alkyl-SO₂NR¹¹R¹², —C₀-C₆ alkyl-SO₂R¹⁰, —C₀-C₆ alkyl-SOR¹³, —C₀-C₆alkyl-OCOR¹³, —C₀-C₆ alkyl-OC(O)NR¹¹R¹², —C₀-C₆ alkyl-OC(O)OR¹³, —C₀-C₆alkyl-NR¹¹C(O)OR¹³, —C₀-C₆ alkyl-NR¹¹C(O)NR¹¹R¹², and —C₀-C₆alkyl-NR¹¹COR¹³, wherein said C₁-C₆ alkyl is optionally unsubstituted orsubstituted by one or more halo substituents; each R⁴ and R⁵ isindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁶ and R⁷ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R⁸ and R⁹ are eachindependently selected from H, halo, C₁-C₆ alkyl, —C₀-C₆ alkyl-Het,—C₀-C₆ alkyl-Ar and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁰ is selected fromH, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; each R¹¹ and each R¹² areindependently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇cycloalkyl, or R¹¹ and R¹² together with the nitrogen to which they areattached form a 4-7 membered heterocyclic ring which optionally containsone or more additional heteroatoms selected from N, O, and S; R¹³ isselected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, —C₀-C₆alkyl-Ar, —C₀-C₆ alkyl-Het and —C₀-C₆ alkyl-C₃-C₇ cycloalkyl; R¹⁴ andR¹⁵ are each independently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl,C₃-C₆ alkynyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Het, —C₀-C₆ alkyl-C₃-C₇cycloalkyl, —C₀-C₆ alkyl-O—Ar, —C₀-C₆ alkyl-O-Het, —C₀-C₆ alkyl-O—C₃-C₇cycloalkyl, —C₀-C₆ alkyl-S(O), —C₁-C₆ alkyl, —C₀-C₆ alkyl-S(O)_(x)—Ar,—C₀-C₆ alkyl-S(O)_(x)-Het, —C₀-C₆ alkyl-S(O), —C₃-C₇ cycloalkyl, —C₀-C₆alkyl-NH—Ar, —C₀-C₆ alkyl-NH-Het, —C₀-C₆ alkyl-NH—C₃-C₇ cycloalkyl,—C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Ar, —C₀-C₆ alkyl-N(C₁-C₄ alkyl)-Het, —C₀-C₆alkyl-N(C₁-C₄ alkyl)-C₃-C₇ cycloalkyl, —C₀-C₆ alkyl-Ar, —C₀-C₆ alkyl-Hetand —C₀-C₆ alkyl-C₃-C₇ cycloalkyl, where x is 0, 1 or 2, or R¹⁴ and R¹⁵,together with the nitrogen to which they are attached, form a 4-7membered heterocyclic ring which optionally contains one or moreadditional heteroatoms selected from N, O, and S, wherein said C₁-C₆alkyl is optionally substituted by one or more of the substituentsindependently selected from the group halo, —OH, —SH, —NH₂, —NH(unsubstituted C₁-C₆ alkyl), —N(unsubstituted C₁-C₆ alkyl)(unsubstitutedC₁-C₆ alkyl), unsubstituted —OC₁-C₆ alkyl, —CO₂H, —CO₂(unsubstitutedC₁-C₆ alkyl), —CONH₂, —CONH (unsubstituted C₁-C₆ alkyl), —CON(unsubstituted C₁-C₆ alkyl)(unsubstituted C₁-C₆ alkyl), —SO₃H, —SO₂NH₂,—SO₂NH (unsubstituted C₁-C₆ alkyl) and —SO₂N (unsubstituted C₁-C₆alkyl)(unsubstituted C₁-C₆ alkyl); R¹⁶ is C₁-C₆ alkyl, —C₀-C₆ alkyl-Aror —C₀-C₆ alkyl-Het; and R¹⁷ is H, C₁-C₆ alkyl, —C₀-C₆ alkyl-Ar or—C₀-C₆ alkyl-Het; or a pharmaceutically acceptable salt or solvatethereof.
 13. The method according to claim 1, wherein the LXR modulatorcomprises a compound of formula (V):

or a pharmaceutically acceptable derivative thereof.
 14. The methodaccording to claim 1, wherein the LXR modulator comprises a compound offormula (VI):

or a pharmaceutically acceptable derivative thereof.
 15. The methodaccording to claim 1, wherein the LXR modulator is an LXR agonist.16-27. (canceled)